supplement monographs -...

Supplement Monographs

654/VITAMIN 812 PDR FOR NUTRITIONAL SUPPLEMENTS

Warren MJ. Finding the final pieces of the vitamin B[2biosynthetic jigsaw. Proc Natl Acad Sci USA.2006; I03( 13):4799-4800.

Watanabe F, Katsura H, Takenaka S, et al. Pseudovitamin BI2is the predominant cobamide of an algal health food, spirulinatablets. J Agric Food Chem. 1999;47:4736-4741.

Weir DG, Scott JM. Brain function in the elderly: role ofvitamin B12 and folate. Br Med Bull. 1999;55:669-682.

Weir DG, Scott JM. Vitamin Bl2 "Cobalamin." In: Shils ME,Olson JA, Shike M, Ross AC, eds. Modern Nutrition in Healthand Disease. 9th ed. Baltimore, MD; Williams and Wilkins;1999:447-458.

Wolters M, Strahle A, Hahn A. Cobalamin: a critical vitamin inthe elderly. Prey Med. 2004;39(6):1256-1266.

Vitamin CDESCRIPTION

The term vitamin C applies to substances that possessantiscorbutic activity and includes two compounds and theirsalts: L-ascorbic acid, commonly cal1ed ascorbic acid, and L-dehydroascorbic acid. Ascorbic acid is the major dietaryform of vitamin C. The terms vitamin C, ascorbic acid, L-ascorbic acid, L-ascorbate and ascorbate are commonly usedinterchangeably.

Vitamin C is a hexose derivative, similar in structure to thesix-carbon sugar glucose. It is an essential nutrient forhumans, and, as pointed out by Linus Pauling in 1970,"differs from other nutrients in that it is required in the dietby only a few species of animals-man, other primates, theguinea pig, an Indian fruit-eating bat, and the red-ventedbarbul and some related species of Passeriform birds." It isalso an essential nutrient for Coho salmon, rainbow trout,carp and some insects. Most other animals, al1 higher plantspecies and probably al1 algal classes can synthesize vitaminC from glucose or other sugars. Molecules similar toascorbic acid are made by some fungi but not by bacteria.Al1 vitamin C requiring animals lack the enzyme L-gulano-gamma-lactone oxidase, the final step in the synthesis ofascorbic acid from glucose. Plants produce large amounts ofascorbic acid to facilitate resistance to the oxidative stressesassociated with the myriad biotic and abiotic chal1engesinherent to photosynthesis.

The major deficiency syndrome of vitamin C is scurvy.Symptoms of scurvy include inflamed and bleeding gums,petechiae, ecchymosis, follicular hyperkeratosis, coiled hairs,perifol1icular hemorrhages, impaired wound healing, dryeyes and mouth (Sjogren's syndrome), arthralgia, jointeffusions, muscle weakness, myalgia, fatigue, depression,frequent infections, anemia, anorexia, diarrhea, and pulmo-

nary and kidney problems that can lead to coma and death.Al1 systems of the body are affected by scurvy.

The antiscorbutic factor was isolated from the ox adrenalcortex in 1927 by the Hungarian biochemist and Nobellaureate Albert Szent-Gyorgyi and his col1eagues, althoughat the time Szent-Gyorgyi didn't know that it was theantiscorbutic factor. In fact, his interest then was not invitamins at al1 but in biological oxidation and reduction, andhe was looking for reducing substances in extracts of theadrenal cortex. What was later to be known as ascorbic acid,Szent-Gyorgyi cal1ed "C XII" since it was the 12thsubstanceprepared and examined in his work on tissue oxidation andthe function of the adrenal cortex. He later discovered that CXII was indeed vitamin C, the antiscorbutic factor, that itsempirical formula was C6Hg06 and that the molecule was acarbohydrate, most likely a sugar derivative. He submitted apaper on his discovery, which he named Ignose (from

"ignosco"-"I don't know" in Latin-and "-ose" to indicatethat it was a member of the sugar family). However, theeditor of the journal rejected that name and also the next onethat Szent-Gyorgyi came up with, "Godnose." The editorsuggested "hexuronic acid" to indicate that it had six carbonsand was a sugar acid similar to glucuronic acid. Szent-Gyorgyi gave in and accepted that name, which shortly wasto change to ascorbic acid. Szent-Gyorgyi actual1y didn'tknow the exact structure of ascorbic acid, which explainsIgnose and Godnose. It was the chemist and also Nobellaureate WaIter Haworth who actual1y deciphered thestructure. Szent-Gyorgyi found a rich source of ascorbic acidin the fruit of the Hungarian red pepper or paprika(Capsicum annuum). He also found some other interestingreducing agents in paprika. He cal1ed these substancesvitamin P. They were the first flavonoids identified. In 1932,the American biochemist Glen King and his colleaguesisolated ascorbic acid from lemon juice, which is where thevitamin C story first began. Well, actual1y lime juice, butclose enough.

Many of the symptoms of scurvy, particularly those havingto do with connective tissue, can be explained by the knownbiochemical roles of vitamin C, particularly its role as acofactor for prolyl and Iysyl hydroxylase, enzymes importantin the formation of col1agen. Col1agen synthesized in theabsence of ascorbic acid-as occurs in scurvy--cannotproperly form fibers, resulting in blood-vessel fragility,among other defects. In the prolyl and Iysyl hydroxylasereactions, as wel1 as in most of the biochemical reactionsascorbic acid participates in, it acts as a reducing agent. Inthese reactions, the vitamin reduces ferric and cupric ions totheir ferrous and cuprous states, forms which are required forthe reactions to proceed.

SUPPLEMENT MONOGRAPHS VITAMIN C /655

Ascorbic acid is also involved in the biosynthesis of otherconnective-tissue components, including elastin, fibronectin,proteoglycans, bone matrix and elastin-associated fibrillin. Italso appears to playa role in collagen gene expression andcellular procollagen secretion.

The fatigue and weakness of scurvy may be due to L-carnitine deficiency. Ascorbic acid is a cofactor for crucialreactions in the carnitine biosynthetic pathway.

Ascorbic acid is involved in modulating iron absorption,transport and storage. It aids in the intestinal absorption ofiron by reducing ferric iron to ferrous iron and may stimulateferritin synthesis to promote iron storage in cells. It isinvolved in the biosynthesis of corticosteroids and aldoste-rone, the conversion of cholesterol to bile acids and itfunctions as a reducing agent for mixed-function oxidases.

For all of this, ascorbic acid is best known for its antioxidantproperties and its possible role in the prevention of certainchronic degenerative disorders, such as coronary heartdisease and cancer. In fact, ascorbic acid may be the mostimportant water-soluble antioxidant in the body.

The daily dietary intake of vitamin C necessary to preventscurvy is about 5 to 10 milligrams. Scurvy is rare indeveloped countries, since most people living in thesecountries typically consume much more than this amount.

About 90% of vitamin C in the average diet comes fromfruits and vegetables. Peppers-sweet green and red peppersand hot red and green chili peppers-are especially rich invitamin C. Other good sources include citrus fruits andjuices, brussels sprouts, cauliflower, cabbage, kale, collards,mustard greens, broccoli, spinach and strawberries. Nuts andgrains contain very little vitamin C. Cooking destroysvitamin C activity.

About 5% to 10% of the total vitamin C content of freshfruits and vegetables is comprised of dehydroascorbic acid.In the case of processed foods, dehydroascorbic acid makesup about 30% of the vitamin C content. D-ascorbic acid(erythorbic acid or isoascorbic acid), the epimer of L-ascorbic acid, is frequently added to food as an antioxidantpreservative. Erythorbic acid has very low vitamin Cactivity.

In addition to being known as ascorbic acid and L-ascorbicacid, vitamin C is also known as 2, 3-didehydro-L-threo-hexano-l, 4-lactone, 3-oxo-L-gulofuranolactone, L-threo-hex-2-enonic acid gamma-lactone, L-3-keto-threo-hexuronicacid lactone, L-xylo-ascorbic acid and antiscorbutic vitamin.It is abbreviated AA. Ascorbic acid is a crystalline, water-soluble substance with a pleasant (to some), sharp acidictaste. Its molecular weight is 176.13 daltons, and its

molecular formula is C6Hg06. The structural formula ofvitamin C is represented as follows:

Vitamin C

The other form of vitamin C is the oxidation product of L-ascorbic acid, L-dehydroascorbic acid or DHA.

VITAMIN C WITH BIOFLA VONoms

Vitamin C with bioflavonoids is a mixture of vitamin C,either as ascorbic acid or as an ascorbate, with flavonoids.Typically, the flavonoids are citrus flavonoids and arederived from lemons, oranges and grapefruits. It is believedthat flavonoids work synergistically with vitamin C. Thisbelief originates from the work and writings of the Hungari-an biochemist Albert Szent-Gyogyi, the co-discoverer ofascorbic acid. Szent-Gyogyi also isolated substances fromcitrus fruits and Hungarian paprika which he called vitaminP. Vitamin P is now referred to as bioflavonoids orflavonoids. Flavonoids are not vitamins.

Szent-Gyogyi believed that bioflavonoids and vitamin Cworked synergistically to maintain blood capillary health andprevent capillary fragility. There is some in vitro evidencethat flavonoids and vitamin C do work synergistically. Onestudy showed that ascorbic acid acts synergistically with theflavonoid quercetin to protect cutaneous tissue cells inculture against oxidative damage induced by glutathionedeficiency. However, there is, as yet, no good evidence thatvitamin C and flavonoids work synergistically in vivo. Arecent study, in cell culture, suggested that flavonoids mayeven inhibit the uptake of vitamin C into cells.

Flavonoids have biological effects independent of anyinteraction with vitamin C. (See various monographs onflavonoids.) Flavonoids from grapefruit include quercetin,naringenin and kaempferol. Lemon flavonoids include hes-peridin (hesperitin 7-0-beta-rutinoside) and eriocitrin (eriod-ictyol 7-0-beta-rutinoside). These flavonoids, along withrutin and others, may be found in vitamin Clbioflavonoidsupplements. Some formulations use flavonoids from thesour orange Citrus aurantium.

EFFERVESCENT VITAMIN C

Effervescent vitamin C is comprised of L-ascorbic acid,citric acid and sodium bicarbonate. It is similar to AlkaSeltzer with ascorbic acid added. When the tablet is placed inwater, the citric acid reacts with sodium bicarbonate to form

656/VITAMIN C PDR FOR NUTRITIONAL SUPPLEMENTS

sodium citrate and carbon dioxide. Also, some sodiumbicarbonate reacts with ascorbic acid to form some sodiumascorbate. Some find effervescent C a more tolerablesupplement than ascorbic acid.

ACEROLA VITAMIN C

Acerola vitamin C is vitamin C derived from acerola fruit.Acerola is the fruit of the small tree or shrub known asMalphighia glabra L. Malphighia glabra is native to theAntilles and northern South America. Acerola is also knownas Barbados cherry, Antilles cherry, West Indies cherry,Puerto Rican cherry, cereso, cereja-das-antilhas and cereja-do-para. In 1945, the Barbados cherry was analyzed byresearchers at the School of Medicine, University of PuertoRico, and was found to be very rich in vitamin C.Interestingly, the analysis was inspired by the use of the fruitfor colds by the local people.

Acerola is one of the richest sources of vitamin C in theworld. The vitamin C content of the fruit depends onripeness, seasons, climates and localities. Content is highestwhen the fruit is still green and lowest when ripe. Thevitamin C content of unripe fruits can range up to 4.7 gramsper 100 grams of fruit or 4.7% and is about 2 grams per 100grams or 2% in very ripe fruit. For comparison, the vitaminC content of a peeled orange is 0.05% or 50 milligrams per100 grams. Acerola also contains flavonoids, other vitamins,such as thiamin, riboflavin, niacin, pantothenic acid and betacarotene, and minerals, such as magnesium and potassium.

Malphighia glabra has also shown active anti-fungal proper-

ties. Folk medicine uses of acerola include treatment of liverailments, diarrhea, dysentery, coughs, colds and sore throats.

ROSE HIP VITAMIN C

Rose hips are the fruit of roses. The rose hip is the swollenovary of the flower which produces seed after the petals of ablossom wither and fall. Once the petals have fallen off arose all that remains attached to the stem is the rose hip.Rose hips are rich sources of Vitamin C. In fact, one species,Rosa rugosa Thunb, contains the highe~t amount of vitaminC of any organism in the world. Rosa rugosa Thunb rosehips can contain up to 7 grams of vitamin C per 100 grams ofrose hips or 7%. Acerola, the next richest source of naturalvitamin C produces up to 4.7% vitamin C, and, forcomparison, the peeled orange contains 0.05% vitamin C.

During World War II, England, Norway and Sweden werefaced with a scurvy crisis. Since the war had restrictednormal shipping, the British could not obtain enough citrusfruit for vitamin C. Children began showing the symptoms ofearly scurvy. The British discovered rose hips to be anexcellent source of vitamin C and made the fruit of the roseinto teas, soups and syrups. The children received these

supplements daily, and this prevented any problem withscurvy.

Rose hips are the major source of natural vitamin C. A fewspecies are used to obtain the vitamin, including Rosacanina, Rosa mosqueta and Rosa rugosa Thunb. In additionto vitamin C, rose hips contain such carotenoids as beta-carotene, lycopene, zeaxanthin, rubixanthin, gazaniaxanthin,beta cryptoxanthin, gamma-carotene, lutein, violaxanthin,and antheraxanthin. They also contain flavonoids, catechins,polyphenols, procyanidins and pectins.

Rose hips have other applications. The oil extracted from itsseeds is included in many cosmetic preparations for its highcontent of alpha-linolenic acid (45%-50%) and linoleic acid(40%). The fruit has been used as food, mainly for preparingjams, teas and alcoholic beverages.

REDUCED-ACIDITY VITAMIN C

Reduced-acidity vitamin C consists of a mixture of 50%ascorbic acid and 50% sodium ascorbate. Some find thisform of vitamin C a more tolerable supplement than ascorbicacid. Since the first pKa of ascorbic acid is 4.2, the pH of themixture dissolved in water would be 4.2. Reduced-acidityvitamin C is also known as buffered vitamin C.

NON-ACID VITAMIN C

Non-acid vitamin C consists of an ascorbate salt of sodiumor calcium which has a neutral pH when dissolved in water.The calcium salt consists of two molecules of ascorbate andone atom of calcium. The molecular formula is

CI2HI4CaOI2' Calcium ascorbate is freely soluble in water.The sodium salt consists of one molecule of ascorbate andone atom of sodium. The molecular formula is C6H7Na06'Some find sodium ascorbate and calcium ascorbate moreacceptable forms for vitamin C supplementation.

ASCORBATE AND VITAMIN C METABOLITES

Ascorbate and vitamin C metabolites refer to marketedvitamin C supplements containing vitamin C in a salt form,typically as calcium ascorbate, and vitamin C metabolites.Vitamin C metabolites can include the aldonic acids L-threonic acid, L-xylonic acid and L-Iyxonic acid. Typically,the vitamin C metabolite present in these products is L-threonic acid, also known as 2, 3, 4-trihydroxy- [threo]butanoic acid. L-threonic acid is usually also present as thecalcium salt or calcium L-threonate, and the percentage ofcalcium L-threonate in the product is usually 1% of theamount of ascorbate. That is, a tablet supplying 500milligrams of ascorbate would supply 5 milligrams of L-threonate.

Ascorbate and vitamin C metabolites are sometimes referredto as metabolite-supplemented ascorbate. Some in vitrostudies have shown that the addition of L-threonate to


ascorbate enhances the transfer efficiency of ascorbate intocells. Animal studies have reported increased absorption andhigher retention of vitamin C when the animals weresupplemented with ascorbate plus threonate than whensupplemented with ascorbate alone. One cell-culture studyshowed that the addition of threonate to ascorbate enhancedthe production of collagenous protein and mineralized tissuewhen compared with ascorbate alone. The authors concludedthat this finding could have relevance with respect to woundhealing and bone regeneration.

Although the in vitro and animal studies appear interesting,what is wanting are well-designed and well-executed clinicaltrials in humans to determine if vitamin C metabolites, suchas L-threonate, positively affect vitamin C status.

ACTIONS AND PHARMACOLOGY

ACTIONS

Vitamin C has antioxidant activity. It may also have anti-atherogenic, anticarcinogenic, antihypertensive, antiviral,antihistaminic, immunomodulatory, ophthalmoprotective andairway-protective actions. Vitamin C may aid in the detoxifi-cation of some heavy metals, such as lead and other toxicchemicals.

MECHANISM OF ACTION

Vitamin C is arguably the most important water-solublebiological antioxidant. It can scavenge both reactive oxygenspecies and reactive nitrogen species. Ascorbic acid or, morespecifically, L-ascorbate is an excellent reducing agent, andit acts as a cofactor in various biochemical reactions toreduce the transition metals, iron and copper.

Ascorbate can be oxidized by most reactive oxygen andnitrogen species thought to play roles in tissue injuryassociated with various diseases. These species includesuperoxide, hydroxyl, peroxyl and nitroxide radicals, as wellas such non-radical reactive species as singlet oxygen,peroxynitrite and hypochlorite. By virtue of this scavengingactivity, ascorbate inhibits lipid peroxidation, oxidative DNAdamage and oxidative protein damage.

Ascorbate is oxidized by reactive oxygen and nitrogenspecies to the semidehydroascorbate radical that is eitherreconverted to ascorbate via the enzyme NADH semidehy-droascorbate reductase or is converted to dehydroascorbate.Dehydroascorbate in turn can be converted back to ascorbatevia glutathione-dependent enzymes or catabolized.

Ascorbate can act as a secondary antioxidant. At least invitro, ascorbate regenerates the major lipid antioxidantalpha-tocopherol from the alpha-tocopheroxyl radical form.Ascorbate may also participate in regenerating and sparingalpha-tocopherol in vivo, though this has not been clearly

demonstrated. Vitamin C does preserve intracellular reducedglutathione concentrations.

The possible anti-atherogenic activity of vitamin C may beexplained in a few ways. Oxidation of low-density lipopro-tein (LDL) is thought to be a key early step in atherogenesis.Vitamin C protects against LDL peroxidation by scavengingperoxyl radicals in the aqueous phase. Vitamin C mayenhance endothelial function by promoting the synthesis ofnitric oxide (also known as NO and EDRF for endothelium-derived relaxing factor) or by preventing its inactivation byscavenging superoxide radicals. Superoxide reacts with nitricoxide to form peroxynitrite. High concentrations of vitaminC are required to prevent the interac~ion of superoxide withnitric oxide, extracellularly. Although such high plasmaconcentrations are feasible if vitamin C is given parenterally,they are likely not to occur with oral administration ofvitamin C.

As noted above, vitamin C helps preserve intracellularreduced glutathione concentrations. This activity likely helpsmaintain nitric oxide levels and potentiates its vasoactiveeffe~ts. Oral vitamin C can ~each high enough concentrationsintracellularly to scavenge superoxide radicals. Thus, intra-cellular sources of superoxide that impair nitric oxide may bescavenged by oral vitamin C. Recently, it has been foundthat ascorbic acid enhances nitric oxide synthase activity byincreasing intracellular tetrahydrobiopterin.

Vitamin C may modulate prostaglandin synthesis to favorthe production of eicosanoids with antithrombotic andvasodilatory activity. The possible sparing and regenerationof alpha-tocopherol by vitamin C could be yet another factorin the vitamin's possible anti-atherogenic action.

Vitamin C's possible anticarcinogenic effects may beaccounted for, in part, by its ability to detoxify carcinogens,as well as its ability to block carcinogenic processes throughits antioxidant activity. Vitamin C can prevent the formationof such carcinogens as nitrosamines in foods and in thegastrointestinal tract and can detoxify such chemical muta-gens and carcinogens as anthracene, benzo[a]pyrene, organo-chlorine pesticides and heavy metals. High concentrations ofascorbic acid in gastric juice may reduce the risk of gastriccancer by inhibiting, as noted, the formation of carcinogenicN-nitroso compounds. Ad~itionally, increased oxidativestress to the gastric mucosa has been reported in Helicobac-ter pylori-associated gastritis, a condition that predisposes togastric cancer. There is preliminary evidence that vitamin Ccan inhibit growth of Helicobacter pylori.

Evidence appears to suggest that vitamin C may have cancer-preventive activity, at least for certain types of cancer.However, the role of vitamin C, if any, in the treatment ofcancer remains very unclear. A cell-culture study of human

65S/VITAMIN C PDR FOR NUTRITIONAL SUPPLEMENTS

breast carcinoma lines showed vitamin C to improve theantineoplastic activity of doxorubicin, cisplatin and paclitax-el. The mechanism of the effect may be pro-oxidant, notantioxidant, activity of the vitamin in potentiating the effectsof these chemotherapeutic agents. Another study suggeststhat the pro-oxidant form of vitamin C may upregulate someof the enzymes involved in DNA repair. This possibleactivity may play some anticarcinogenic role. Recently, ithas been found that ascorbic acid enhances arsenic trioxide-induced cytotoxicity in multiple myeloma cells. Again, thismay be attributed to a pro-oxidant effect of vitamin C.Increasing reduced glutathione (OSH) levels attenuatesarsenic trioxide-induced cytotoxicity. Decreases in OSHhave been associated with ascorbic acid metabolites. Arsenictrioxide is an anticancer drug with multiple actions.

Vitamin C may have anti-hypertensive activity in some. Themechanism of this possible effect is a matter of speculation.Some in vitro studies show that vitamin C increases thesynthesis of the vasodilatory prostaglandin POEI. However,this may not have relevance in the regulation of vasculartone in humans. As observed above, vitamin C may helpmaintain nitric oxide levels and potentiate its vasoactiveeffects. There is an indication that vitamin C may improveendothelial-dependent vasodilation in those with essentialhypertension, as well as in those with hypercholesterolemia,and may help restore nitric oxide-mediated flow-dependentvasodilation in those with congestive heart failure.

There is some evidence that vitamin C inhibits the replica-tion of human immunodeficiency virus 1 (HIV-I) in vitro.One study showed upregulation of the expression of glucosetransporter 1 (Olut!) in HIV-infected cells Olutl is one ofthe transport proteins for ascorbic acid. Increased cellularconcentrations of ascorbate may be toxic to HIV-infectedcells due to degradation of the viral nucleic acid by theaction of the pro-oxidant form of vitamin C. The mechanismof the anti-HIV effect of the vitamin in vitro, however, isunclear, as is the relevance of this finding to HIV-positiveindividuals.

There is no evidence that vitamin C affects the replication ofthe viruses that cause the common cold in vivo. There issome evidence that vitamin C supplementation decreases theincidence, severity and duration of common cold symptomsin some. It is thought that this is due, at least in part, toantihistaminic activity of vitamin C.

The possible immunomodulatory activity of vitamin C mayalso be due, in part, to an antihistaminic effect of thevitamin. Vitamin C may enhance neutrophilic chemotaxisindirectly by reducing immunosuppressive effects of hista-mine. Some studies have shown that vitamin C, in vitro,enhances mitogen-stimulated lymphocyte proliferation, de-

layed-type hypersensitivity (DTH) response to skin antigens,natural killer cell activity and neutrophil chemotaxis. How-ever, other studies have shown no effect of the vitamin onthese and other indices of immune function.

Some studies suggest a protective effect of vitamin Csupplementation against cataracts. Age-related lens opacitiesare thought to be due to oxidative stress. Ocular tissueconcentrates yitamin C, and the antioxidant action of thevitamin could account for its possible effect in protectionagainst cataracts.

Vitamin C may protect against asthma and other obstructivepulmonary diseases, as well as protect the airways againstthe effects of allergens, viral infections and irritants in some.Allergens, viruses and irritants, including ozone, nitrogenoxides and sulfur oxides, subject the airways to increasedoxidative stress which can lead to bronchoconstriction. Thepossible protective action of vitamin C appears clearly due toits antioxidant properties.

The antioxidant properties of vitamin C can also account forits role in protecting against the tissue-damaging effect ofsome toxic chemicals and heavy metals. High serum levelsof ascorbic acid have been reported to be associated with adecreased prevalence of elevated blood lead levels. Themechanism of the possible lead-lowering action of vitamin Cis unclear. One study compared the chelating properties ofascorbic acid and the known lead-chelating agent EDTA andfound them to have equivalent activity with respect to lead.

PHARMACOKINETICS

Absorption of vitamin C from the lumen of the smallintestine depends on the amount of dietary intake. At adietary intake of 30 milligrams daily, the vitamin is nearlycompletely absorbed from the lumen of the small intestineinto the enterocytes. At an intake of 30 to 180 milligramsdaily, about 70% to 90% is absorbed. About 50% of a singledose of 1 to 1.5 grams is absorbed. The percentage of asingle dose absorbed decreases with increasing amounts. Forexample, only 16% of a single dose of 12 grams is absorbed.Maximum vitamin C absorption of large doses is attained byingestion of several spaced doses throughout the day ratherthan by a single large dose. Further, sustained-release formsof large doses will give a higher efficiency of absorptionthan an equivalent dose that is not sustain-released. The typeof food consumed does not appear to affect the absorption ofsupplemental vitamin C or vitamin C found in food.

The intestinal absorption of vitamin C from foods and fromsupplements, up to about 500 milligrams, occurs via asodium-dependent active transport process. At doses higherthan 500 milligrams, diffusion processes come into play. Themajor intestinal vitamin C transporter is SVCTI (sodium-dependent vitamin C transporter 1). Some ascorbic acid may


be oxidized to dehydroascorbic acid and transported intoenterocytes via glucose transporters. Dietary dehydroascor-bic acid is absorbed from the lumen of the small intestineinto the enterocytes in such a manner. All dehydroascorbicacid within the enterocytes is reduced to ascorbic acid viareduced glutathione, and ascorbic acid leaves the enterocytesto enter, first, the portal and, subsequently, the systemiccirculation. Ascorbic acid is distributed to the various tissuesof the body.

Higher levels of ascorbic acid are found in the pitUitarygland, the adrenal glands, the various white blood cells andthe brain. Ascorbic acid itself cannot cross the blood-brainbarrier. In order to enter the brain, ascorbic acid is firstoxidized to dehydroascorbic acid or DHA. DHA is thentransported across the blood-brain barrier by facilitativediffusion via glucose transporter 1 (GLUTl). DHA is nexttransported through GLUTl at the surface of the blood-brainbarrier endothelial cells. DHA is transported out of theendothelial cells through GLUTl. DHA in the brain isreduced to ascorbic acid. Ascorbic acid, once formed, isessentially trapped in the brain since it cannot be transportedthrough GLUTl.

Ascorbic acid appears to be transported into intestinal cells,liver cells and kidney cells by a sodium-dependent activetransport process via SVCTl (sodium-dependent vitamin Ctransporter 1). The transporter SVCT2 (sodium-dependentvitamin C transporter 2) appears to aid in the transport ofvitamin C into the aqueous humor of the eyes. Uptake ofascorbic acid into neutrophils appears to be by facilitativediffusion via GLUTl.

Regarding the metabolism of ascorbic acid, it is oxidized todehydroascorbic acid which can either be reduced back toascorbic acid or hydrolyzed to diketogulonate. Other metab-olites include oxalic acid, threonic acid, L-xylose andascorbate-2-sulfate. The principal route of excretion ofascorbic acid and its metabolites is via the kidney. In order tomaintain ascorbic acid homeostasis, very little unmetabo-lized ascorbate is excreted with dietary intakes up to about80 milligrams daily. Renal excretion of ascorbate increasesproportionately with higher doses. As mentioned earlier, asthe dose of supplemental ascorbic acid increases, thepercentage of its absorption proportionately decreases. Con-sequently, there is significant fecal excretion of ascorbic acidwith high supplemental intakes of the vitamin.

INDICATIONS AND USAGE

Vitamin C may be helpful in chronic diseases characterizedby oxidative damage to biological molecules. Thoughvitamin C also has a pro-oxidant potential under somecircumstances, fears raised in that regard in recent yearsappear overblown. There is currently no credible evidence

for oral vitamin C pro-oxidant damage in humans except,possibly, in rare circumstances involving iron overload.

Vitamin C's antioxidant activity, on the other hand, is wellestablished, and that activity may be helpful in the preven-tion of some cancers and cardiovascular disease. Vitamin Cmay also be helpful in protecting against some of the lipidoxidation caused by smoking. Vitamin C's demonstratedability to reduce some forms of oxidative DNA damage andindications that it may also reduce protein oxidation undersome circumstances further suggest that it may be of benefitin smokers and some with chronic stress and disease, ingeneral. Considerable excitement has attended recent in vitroand in vivo animal research findings that injected vitamin Cmay have potent anticancer effects in a number of estab-lished malignancies, renewing interest in vitamin C not onlyas a possible cancer preventive but also as a potentiallypotent cancer interventive. These same findings have sug-gested that Vitamin C may also have some anti-infectivepotential greater than previously acknowledged.

Vitamin C may also be useful as an immune stimulator andmodulator in some circumstances. Claims that it is a "cure"for common colds are unsubstantiated, although severalstudies have shown that vitamin C can significantly reducethe duration and severity of colds in some and reduceincidence in others. There is also preliminary evidence thatvitamin C can be useful in ameliorating some otherrespiratory infections.

Vitamin C may help prevent cataracts.

Recently it was demonstrated that vitamin C can inhibitgrowth of Helicobacter pylori and may thus be protectiveagainst some ulcers and gastric carcinomas. There is also thesuggestion in a recent report that low serum levels ofascorbic acid may be associated with a higher incidence ofgall bladder disease in women. In another recent report,vitamin C supplementation was associated with reduced riskof reflex sympathetic dystrophy after wrist fracture. It maybe of benefit in some bum victims and may be helpful,generally, in promoting wound healing and gum health

Vitamin C has previously shown some benefit in someindividuals with asthma, although a recent review concludedthat the vitamin C asthma data remain inconclusive. Whetherit might also be useful in some other airway disorders/impairment, such as those present in cystic fibrosis, remainsunclear and largely untested. There is a preliminary indica-tion that it might be helpful in Charcot-Marie-Tooth disease,the most common hereditary peripheral neuropathy. There isno convincing evidence that it is useful in Alzheimer'sdisease. A strong inverse association between plasmavitamin C levels and type 2 diabetes mellitus risk has been

660 IVITAMIN C PDR FOR NUTRITIONAL SUPPLEMENTS

noted recently. Effects on muscle and endurance perfor-mance are unclear.

RESEARCH SUMMARY

Vitamin C's antioxidant effects are well established. It hasbeen reported to protect plasma lipids from oxidativedamage. It also significantly protects DNA and protein fromvarious oxidative processes, as demonstrated in numerousstudies.

There is still controversy around claims that vitamin C canbe a dangerous pro-oxidant in humans. These claims are nowgenerally discounted, and the research that led to these fearshas been widely challenged as being flawed in a number ofrespects. One researcher recently reviewed this controversyand concluded: "there is nothing in current data to worrymembers of the public who take ascorbate supplements."

Other researchers have also recently reviewed this controver-sy, noting that in vitro observations of DNA damage arisingin the presence of vitamin C and redox-active transitionmetal ions are unlikely to have relevance in vivo. Thedamaging effect demonstrated in vitro, ,these researcherspoint out, "requires the availability of free, redox-activemetal ions and a low ratio of vitamin C to metal ion,conditions unlikely to occur in vivo under normal circum-stances. Furthermore, it was shown recently that in biologi-cal fluids such as plasma, vitamin C acts as an antioxidanttoward lipids even in the presence of free, redox-active iron. . . there is no convincing evidence for'a pro-oxidant effectof vitamin C in humans." However, although this is the casefor orally administered vitamin C, the vitamin may indeedhave a pro-oxidant effect when administered parenterally(see below).

On the other hand, vitamin C's antioxidant activity is markedand appears to play an important role in its possiblecardioprotective activity. Several studies have shown thatvitamin C, either alone, or in combination with othernutrients significantly inhibits LDL-cholesterol oxidation.This effect is most consistent when vitamin C is combinedwith vitamin E and/or beta-carotene, but it has also beenobserved when vitamin C is used alone. In the latter case,some hypothesize that it works by sparing or recyclingvitamin E, an activity that has been obserVed in Ivitro.Resultshave been mixed in smokers in whom lipid oxidation is aserious problem. One of the better designed studies, utilizinga particularly sensitive measure of lipid oxidation, found thatheavy smokers benefited from 2,000 milligrams of vitamin Cadministered for only five days, as measured by a significantreduction in a specific lipid oxidation marker, the F2isoprostane 8-epi-PGFralpha.

Where there have been discrepancies in results from lipid(and other) biomarkers studies, some researchers attribute

these, in part, to the failure of some investigators todifferentiate between subjects whose tissues are alreadysaturated with vitamin C at baseline and those whose tissuesare not thus saturated. Even dietary, non-supplemental,vitamin C intake, they argue, can readily result in saturationsufficient to rule out further reductions in oxidative damage,no matter what supplemental dose is administered.

Vitamin C supplementation has also been reported, in somestudies, to significantly reduce total serum cholesterol. Someothers have not shown this benefit. And there have beenseveral observational reports associating high plasma vita-min C concentrations with higher levels of HDL-cholesterol.

Platelet aggregation has been reduced in two studies utilizing2,000-3,000 milligrams of vitamin C daily for one to sixweeks. No effect was noted on platelets in another studyusing 250 milligrams of vitamin C daily for eight weeks.Leukocyte adhesion to endothelium, an activity implicated inatherogenesis, was significantly inhibited in smokers receiv-ing 2,000 milligrams of vitamin C daily for 10 days.

Several studies have shown that vitamin C has positiveeffects on hypertension. Here, too, there have been someconflicting results, but the preponderance of evidencesuggests a positive effect. Epidemiological studies alsoconsistently show that lower vitamin C intake is associatedwith hypertension. In one recent randomized, double-blind,placebo-controlled study, hypertensive patients receivedplacebo or 500 milligrams of vitamin C daily for 30 days.Vitamin C resulted in a 13 mmHg reduction in systolic bloodpressure. Placebo had no effects.

Several other studies have shown that both oral administra-tion (l,000-2,000'milligrams) and intra-arterial infusion withvitamin C can exert significant, positive effects on vasodila-tion in coronary artery disease patients. Similar benefits havebeen found in several other test groups, including smokersand those with both type I and type 2 diabetes.

Vitamin C's potential impact on incidence of heart attack,stroke and death related to cardiovascular disease may bequite significant according to the findings of severalepidemiological studies. In an analysis of findings from theFirst National Health and Nutrition Examination Survey,researchers found that "the relation of the standardizedmortality ratio (SMR) for all causes of death to increasingvitamin C intake is strongly inverse for males and weaklyinverse for females." Among males with the highest vitaminC intake, SMRs were 0.65 for all causes, 0.78 for all cancersand 0.58 for all cardiovascular disease. Among females withthe highest vitamin C intake, SMRs were 0.90 for all causes,0.86 for all cancers and 0.75 for all cardiovascular disease.Comparisons were made relative to the U.S. white popula-tion; for which the SMR was defined as 1.00.


In a 20-year follow-up study of a cohort of randomlyselected elderly people in Britain, Scotland and Wales,mortality from stroke was highest in those with the lowestvitamin C status, as measured by dietary intake and plasmaascorbic acid concentration. Adjustments were made for age,sex and established cardiovascular risk factors. The associa-tion noted was independent of social class and other dietaryvariables. No association was found in this study betweenvitamin C status and risk of death from coronary arterydisease, but the researchers noted this may have been due tothe age of their observed population. "Factors that maypredict premature death from coronary heart disease maybecome less important when measured in a population ofelderly survivors," they noted. The subjects in this cohortwere 65-74 years of age.

Recently, a five-year prospective population study of 1,605Finnish men aged 42-60, who were free of atheroscleroticheart disease at baseline, concluded with these results: risk ofmyocardial infarction was considerably higher among thosewith the lowest baseline plasma vitamin C concentrationsthan among those with higher levels; 13.2% of those with thelowest levels suffered MIs versus 3.8% of those with higherlevels.

What made this study particularly significant was its findingthat increased risk of MI, in relation to plasma vitamin Cconcentrations, was confined to that group of subjects whowere frankly deficient in vitamin C. In men with normal tohigh concentrations, there was no increased risk. This mayhave significance for some other studies that found nobenefit from vitamin C in reducing cardiovascular diseaserisk.

It has been established by prior research that the Finnishpopulation suffers high mortality from coronary heart diseaseand that many Finnish men have low plasma ascorbateconcentrations. A reviewer of the Finnish study thusconcluded that the finding in this study "that only individualswho are vitamin C-deficient are at increased risk mayexplain to some extent why no significant relationship wasobserved in many studies of relatively well-nourishedpopulations. "

ThIs observation might apply, some believe, to the Nurses'Health Study and the Health Professionals' Study, bothfollow-up investigations that showed a relationship betweenincreased vitamin E intake and reduced coronary heartdisease risk but no similar relationship with respect tovitamin' C.

As the reviewer further observed: "Both of these studiesinvolved generally health-conscious study subjects. The vastmajority of antioxidant-disease studies, even controlledintervention studies, involve generally healthy, well-nour-

ished populations, primarily because these populations aremuch easier to study. The Finnish study results, therefore,provide a special perspective that may help us to understandthe mixed results from past studies and better plan futurestudies."

Vitamin C has, experimentally, demonstrated an ability toprotect against various cancers, most likely through itsability to inhibit DNA oxidation, through reactive nitrogenspecies scavenging and other antioxidant actions, as well asthrough its possible effects on the immune system, amongother activities. There are numerous epidemiological andcase-control studies showing a consistent relationship be-tween higher dietary intakes of vitamin C and lowerincidence of cancer, particularly colorectal, stomach, lung,breast, esophageal, oral cavity and larynx-pharynx cancers.In one review of 75 epidemiologic studies, 54 foundsignificant evidence of reduced cancer risk in those withhigher dietary vitamin C intake.

Several in vitro and animal studies have demonstratedbenefits. Results of some animal studies suggested thatvitamin C therapy could reduce the toxicity and/or increasethe effectiveness of some standard cancer therapies. Current-ly some researchers have expressed fear that vitamin C mightreduce the effectiveness of some radiation and cancerchemotherapies by reducing their toxicity in cancer cells, aswell as in normal ells. This idea has neither been confirmednor refuted in animal or human studies and requires furtherinvestigation. Meanwhile, other researchers have expresseddoubts about this hypothesis. They point out, as noted above,that several experimental studies indicate that high doses ofvitamin C not only protect normal cells from toxic cancertherapies but may simultaneously fight the cancer cells, aswell.

Many population studies have found evidence of a vitamin Cprotective effect against some cancers. Some other studies,however, have been negative. One group of researchersreported a significant 29% reduction in risk of all cancer inmales consuming 113 milligrams or more of vitamin C daily,compared with males consuming less than 82 milligramsdaily. Another found that consumption of 300 milligrams ofvitamin C daily, derived from diet and from supplementa-tion, was associated with a 21% reduction in risk from allcancers in men compared with daily consumption of lessthan 49 milligrams daily.

In a review of many of the epidemiological studies, theauthors noted: "Interestingly, virtually all of the studies inwhich vitamin C intakes were greater than 87 milligrams aday in the lowest intake group (quantile) found no ornonsignificant effects on cancer risk reduction with higher


intakes of vitamin C . . . . More studies investigating cancerrisk in persons with lower vitamin C intakes are warranted."

Studies of those using higher dose vitamin C supplementshave generally not shown protective effects against cancer,"possibly," these reviewers observed, "because the dietaryintake of vitamin C was already sufficient for tissuesaturation." Intervention trials with high dose vitamin C havealso been mostly negative.

At present, there is evidence that vitamin C helps protectagainst a number of cancers. Generally amounts sufficient toexert preventive activity can be obtained from a diet thatincludes several servings of fruits and vegetables daily and/or through low-dose vitamin C supplementation.

Recently evidence has emerged that vitamin C may also havea potent interventive potential in cancer-but not via diet!supplementation but, rather, via injection. A few years ago,several researchers from various branches of the NationalInstitutes of Health conducted an in vitro study, the results ofwhich surprised many in the research world. These research-ers exposed human Burkitt's lymphoma cells to concentra-tions of ascorbic acid equal to what they determined could beachieved through injection (but not through oral administra-tion). They cited pharmacokinetics studies that had demon-strated that 10 grams of ascorbic acid given intravenouslycan produce at least a 25-fold higher plasma concentrationthan can the same dose given orally. Their results demon-strated that the much higher levels achievable through theintravenous route effectively killed cancer but not normalcells, acting as a pro-drug to deliver extracellular hydrogenperoxide as the selective killing agent. Why the hydrogenperoxide generated by the ascorbate does not affect normalcells remains unknown. The cancer cell death occurred byapoptosis and pyknosis/necrosis. The researchers hypothe-sized that the hydrogen peroxide might target cancer cellularmembrane lipids forming hydroperoxides or reactive inter-mediates that are quenched/repaired in normal cells but notin cancer cells. In any case, the researchers concluded thatthese findings have "major therapeutic implications" and notonly for cancer but also possibly for numerous infections thathave been shown to be susceptible to hydrogen peroxideattack. (Among these: some viruses, including hepatitis C.)They pointed as well to a possible therapeutic application ofvitamin C in patients with chronic granulomatous disease-again via injection, not oral administration.

Very recently, some of these same researchers generatedheadlines around the world when they extended their in vitroobservations to in vivo animal cancer models, again withnotable positive results. In these experiments, the researchersdelivered pharmacologic parenteral doses of ascorbate tomice bearing aggressive tumor xenografts. Single doses of

the ascorbate produced significant, sustained ascorbateradical and hydrogen peroxide formation selectively withininterstitial fluids of tumors but not in blood. Daily adminis-tration of ascorbate significantly reduced growth rates ofestablished ovarian, pancreatic and glioblastoma tumors inthe mice. The researchers showed as well that the samepharmacologic concentrations of ascorbate were easilyachieved via vitamin C injection in humans. They concludedthat ascorbate as a pro-drug may have benefits in cancers"with poor prognosis and limited therapeutic options."Clearly further research is indicated and warranted.

Vitamin C has shown a variety of activities in the immunesystem. It has been shown, in animal and in vitro studies, tofavorably modulate lymphocytes and phagocytes. It canregulate natural killer cells under some circumstances andaffect production of cytokines, antibodies and complementcomponents.

Because supplemental vitamin C was not shown, in severalstudies, to reduce the incidence of the common cold, manyconcluded that it was of no use whatever in colds. That isstill the impression of some physicians, but it is probably anerroneous one. First, a few studies have, in fact, shown areduction in incidence of colds. Most studies have been donein normally nourished subjects in western countries; thesehave, typically, shown no effect on incidence. But in threetrials of subjects under acute physical stress, vitamin Csupplementation resulted in a 50% reduction in commoncold incidence. And in four British trials, there was anaverage 30% reduction in incidence among those receivingvitamin C. Dietary vitamin C intake is known to be low inthe UK.

Placebo-controlled trials have consistently found that supple-mental vitamin C, in doses of I gram or greater daily,alleviated the duration and severity of cold symptoms. Inseveral of these studies, the alleviation has been significant.For unexplained reason, there seems to be a greater effect inchildren than in adults and possibly, a greater effect in malesthan in females. The best results have been obtained with 2-gram (or greater) daily doses. There was a 6% medianreduction in cold duration in five studies in which adultswere administered I gram of vitamin C daily. There was amedian decrease of 26% in two studies of children given 2grams of vitamin C daily. A recent review found noconsistent evidence for vitamin C reducing the incidence ofcolds in the normal population, but it did find a strongpositive effect among those exposed to brief periods ofstrenuous physical exercise and/or cold environments. Ananalysis of six trials involving a total of 642 skiers, marathonrunners and soldiers on sub-arctic exercises indicated thatvitamin C supplementation cut the risk of colds in half. Thereviewers called for more therapeutic trials to further clarify


the vitamin's potential in treating/preventing/shortening

colds.

Vitamin C has also been found to be of benefit in patientswith pneumonia and bronchitis. Incidence of pneumonia wassignificantly reduced in three controlled vitamin C studies,and substantial vitamin C treatment benefit was noted inelderly UK patients hospitalized with pneumonia orbronchitis.

There is evidence that supplemental vitamin C can inhibit thegrowth of Helicobacter pylori in both in vitro and animalstudies. Thus it might have the potential to reduce theincidence of H. pylori-induced ulcers and subsequent gastriccarcinoma. In vitro, high concentrations of vitamin Cinhibited up to 90% of H. pylori growth. There was alsosignificant inhibition of growth in animal experiments usingoral administration of vitamin C.

High intake of vitamin C is strongly associated with reducedincidence of cataracts, according to the findings of case-control studies. In one study, intake of 300 milligrams ormore per day was associated with a 70% reduction in risk.Another study found a 75% reduction in risk with dailyintake of 490 milligrams or more per day, compared withintakes less than 125 milligrams per day. An interVentionstudy using 120 milligrams of vitamin C daily produced anonsignificant reduction in cataract risk of 22%, but asignificant 36% reduction was observed in the same trial insubjects who consumed a multivitamin/mineral supplement.

Laboratory work has shown that vitamin C can slowchemical reactions that lead to cataracts by causing variouslens proteins to aggregate. This has been demonstrated inanimal work and in the human eye.

In a study of women who took vitamin C for at least tenyears, incidence of cataracts was significantly reducedcompared with controls who did not take vitamin C. Thevitamin C-supplemented women were only 23% as likely todevelop cataracts compared with the women who did nottake supplements. In women not taking supplements, meandaily dietary intake of vitamin C was 130 milligrams perday, about twice the recommended intake but still less thanone-third the average of women taking supplements.

Recently, serum ascorbic acid levels were found to beinversely related to prevalence of gall bladder disease amongwomen but not among men. Previously, it was shown thatvitamin C-deficient guinea pigs have a high incidence ofgallstones. Further clinical investigation is warranted.

In another recent study, this one a double-blind, placebo-controlled trial of vitamin C in patients with conservativelytreated wrist fractures, treatment with 500 milligrams ofvitamin C daily for 50 days significantly reduced the

incidence of reflex sympathetic dystrophy (RSD). Follow-upcontinued for one year. The researchers proposed that "thissimple and cheap means of prevention could also be usefulin the prophylaxis of RSD after other injuries, such as traumaof the foot or ankle, talar and calcaneal fractures, or cruralfractures."

It was the use of vitamin C as an antioxidant therapy indermal burns that led the researchers to believe that anantioxidant therapy might also be of benefit in preventingpost-traumatic dystrophy (after wrist fracture). Researchershave found that vitamin C helps protect endothelial cells andreduces capillary permeability by reducing lipid peroxidationafter burns. Some of these same mechanisms apparentlyaccount for reported beneficial effects of vitamin C in avariety of wounds, in addition to burns. There is someevidence that supplemental vitamin C may decrease perme-ability of gum surface tissue and may, by that and othermechanisms, help protect against periodontal gum disease.

Some studies have indicated that vitamin C can be of benefitin alleviating some of the symptoms of asthma. In one ofthese studies, a 500-milligram dose of vitamin C taken 90minutes before exercise reduced bronchial spasms in someasthma sufferers. In another study, I gram of ascorbate dailyreduced airway reactivity to various harmful inhalants inasthmatics. A recent review of the vitamin C asthmaliterature, however, found no convincing evidence (fromrandomized control trials) that the vitamin has an establishedrole in the treatment of this disorder. The authors concludedthat the data gathered to date are insufficient upon which tobase any conclusion.

There is no evidence that vitamin C is helpful in Alzheimer'sdisease. Vitamin C's role in muscle metabolism and anypossible benefit in endurance training remain to be delin-eated or demonstrated. In one recent study, oral administra-tion of vitamin C was said to decrease muscle mitochondrialbiogenesis and hamper training-induced adaptations inendurance performance in a small clinical trial. Oral doses ofI gram daily were administered over an eight-week trainingperiod. Some of the findings of this study were derived froma concurrent animal study. Again, these data are insufficientfor reaching any meaningful conclusion.

Recently, a strong inverse association was noted betweenplasma vitamin C levels and the risk of new-onset type 2diabetes mellitus. Fruit and vegetable intake, to a lesserdegree, was also inversely associated with this risk.

Finally, an intriguing study has suggested that ascorbic acidmight be helpful in the treatment of Charcot-Marie-Toothdisease, the most common hereditary peripheral neuropathy,affecting 1 in 2,500 people. The only other treatments forthis disease are physical rehabilitation and corrective sur-


gery. This is a disease characterized by abnormal myelina-tion of the peripheral nerves with consequent progressiveweakness and atrophy of the distal muscles of the limbs. Inthis mouse model of the disease, ascorbate, a knownpromoter of myelination, substantially ameliorated the condi-tion, reducing the expression of what is believed to be theresponsible gene to a level below that required to induce thedisease phenotype. The researchers, noting the absence ofgood alternatives, concluded that vitamin C "offers animmediate therapeutic possibility for patients with thedisease. "

CONTRAINDICATIONS, PRECAUTIONS, ADVERSE REACTIONS

CONTRA INDICA TIONS

Vitamin C is contraindicated in those with known hypersen-sitivity to the substance or to any ingredient in a vitamin C-containing product.

Rose hip vitamin CRose hip vitamin C is contraindicated in those with knownhypersensitivity to rose hips. There are reports of allergicreactions in those working with rose hips.

PRECAUTIONS

Although oxalic acid is formed when ascorbic acid ismetabolized, this is highly unlikely to cause renal problemsin healthy individuals without preexisting renal problems orwho are not predisposed to increased crystal aggregation.Those with preexisting kidney stone disease or a history ofrenal insufficiency, defined as serum creatine greater than 2and/or creatinine clearance less than 30, should exercisecaution in the use of higher than RDA amounts of vitamin C(see Dosage and Administration).

Ascorbic acid is involved in modulating iron absorption andtransport. It is highly unlikely that healthy individuals whotake supplemental vitamin C will have any problem with ironoverload. On the other hand, those with hemochromatosis,thalassemia, sideroblastic anemia, sickle cell anemia anderythrocyte G6PD deficiency might have such a problem ifthey use large amounts of vitamin C.

Pregnant women and nursing mothers should avoid usingsupplemental doses of vitamin C higher than RDA amounts.

ADVERSE REACTIONS

In healthy adults, oral doses up to 3 grams daily of vitamin Care unlikely to cause adverse reactions. The most commonadverse reaction in those who take oral doses greater than 3grams daily are gastrointestinal and include nausea, abdomi-nal cramps, diarrhea and flatulent distention. These reactionsare attributed to the osmotic effect of unabsorbed vitamin Cpassing through the intestine. Some advocates of megadosevitamin C use recommend titrating the daily dose of vitaminC to what they refer to as "bowel tolerance", i.e., the point at

which the user begins experiencing diarrhea. This is notrecommended.

Rare adverse reactions have been reported in healthyindividuals taking high oral doses of vitamin C. Theseinclude elevation of serum glucose in an adult male taking4.5 grams daily, a gastrointestinal obstruction in a 66-year-old woman taking 4.5 grams daily of ascorbic acid andesophagitis in one person taking a single 500 milligram dose.Daily ingestion of high-dose vitamin C is generally regardedas largely innocuous. However, vitamin C-induced hyper-qxaluria, although rare, has been reported. It was reported(July 2008) that a patient admitted to a hospital in NewZealand developed acute renal failure secondary to vitaminC-induced hyperoxaluria, from which the patient died.

INTERACTIONS

DRUGSAluminum-containing antacids: The intake of large doses ofvitamin C used at the same time as aluminum-containingantacids has been reported to increase urinary aluminumexcretion, suggesting increased aluminum absorption fromthese antacids. However, this is not well documented.

Aspirin: Chronic use of high dose aspirin may lead toimpaired vitamin C status.

Chemotherapeutic agents: Vitamin C may potentiate theantineoplastic activity of cisplatin, doxorubicin and paclitax-el. It may also help ameliorate the cardiotoxic effect ofdoxorubicin and the nephrotoxic effect of cisplatin. This isbased on in vitro and animal studies. There is a concern bysome researchers that supplemental doses of vitamin C maydiminish the efficacy of some chemotherapeutic agents.Ascorbic acid has been found to enhance arsenic trioxide-induced cytotoxicity in multiple myeloma cells. It has alsobeen found to overcome drug resistance in myeloma and tosignificantly increase the anti-myeloma effects of botharsenic trioxide and melphalan in cell culture models and inanimal models. Arsenic trioxide is an anticancer drug withmultiple actions, and a number of clinical studies areexamining the possible synergistic effect that vitamin C mayhave when administered along with arsenic trioxide. In all ofthese cases, vitamin C is given parenterally and not orally.

However, a recent report found that vitamin C mayantagonize the cytotoxic effects of a number of antineoplas-tic drugs, including doxorubicin, vincristine, methotrexate,cisplatin and imatinib mesylate. This was based on apreliminary in vitro study and requires follow-up before anyconclusions can be drawn.

Estrogen: Ascorbic acid may enhance 17 beta-estradiolinhibition of oxidized LDL formation.

SUPPLEMENT MONOGRAPHS

Propranolol: Ascorbic acid may affect both the absorptionprocess and the first pass metabolism of propranolol. Heartrate has been found to decrease less when propranolol wasadministered with ascorbic acid, when compared to controls.The interaction has little biological importance.

Vitamin C/Bioflavonoid combinations and drugs that inhibitcytochrome P-450 3A4: Preparations containing grapefruitflavonoids may interact with some drugs. Some drugs haveup to a three-fold greater bioavailability when coadminis-tered with grapefruit juice. It is thought that the grapefruitflavonoid naringenin plays some role in this effect. Naringe-nin and/or other substances found in grapefruit juice inhibitcytochrome P-450 3A4 (CYP 3A4). Drugs affected includethe calcium channel blocker felodipine, as well as carbamaz-epine, cyclosporine, lovastatin, simvastatin, saquinavir andnisoldipine. Those taking these drugs need to exercise somecaution in the use of any grapefruit products.

NUTRITIONAL SUPPLEMENTS

Copper: One study showed that high doses of vitamin Cnegatively affected ~opper status in men. Other studies havenot shown such effects.

Flavonoids: Vitamin C may act synergistically with variousflavonoids. This is the basis of combining flavonoids withvitamin C in some supplements. However, it is not known ifany synergism occurs to any extent in humans. There is areport that the vitamin acts synergistically with the flavonoidquercetin to protect cutaneous cells against oxidative dam-age. The study was performed with cells in culture. There areother reports, again from cell culture studies, that certainflavonoids such as quercetin and hesperetin may inhibit th~uptake of vitamin C into cells.

Glutathione: Ascorbic acid may help maintain reducedglutathione levels in cells.

Iron: Vitamin C used concomitantly with nonheme ironsupplements may increase the uptake of iron. This may causeproblems in those with high iron stores or with propensityfor iron overload, such as those with hemochromatosis,sideroblastic anemia, sickle cell anemia, thalassemia anderythrocyte G6PD deficiency.

Selenium: One animal study reported that the protectiveeffect of selenite in tumorogenesis was nullified by, vitaminC. The chemopreventive action of selenomethionine, a formof selenium derived from foods, was not affected by'thevitamin. Selenite may be reduced by vitamin C to a form thatis not available for uptake by tissue.

Vitamin E: Vitamin C may regenerate or spare d-alpha-tocopherol. However, this is based on in vitro and animalstudies. It is not yet known if this occurs in humans and, if itdoes, to what extent.

VITAMIN C /665

LABORATORY TESTS

Bilirubin assay: High intakes of vitamin C may cause falselyelevated bilirubin values.

Creatinine assay: Large intakes of vitamin C may causefalsely elevated urine and serum creatinine levels. However,this is not well documented.

Glucose assay: Large intakes of vitamin C may cause falsepositive glucose readings measured by copper reductionmethods (e.g., Clinitest) and false negative glucose results asmeasured by the oxidase methods (e.g., Clinistix and Tes-Tape).

Guaiac assay for occult blood: Intakes of vitamin C greaterthan I gram daily may cause a false negative guaiac test.

OVERDOSAGE

There are no reports of vitamin C overdosage In theIiterature.

DOSAGE AND ADMINISTRATION

A dose of 200 milligrams daily is almost enough tomaximize plasma and lymphocyte levels. Doses of vitamin Cvary from those equivalent to the RDAs up to 5 to 10 gramsdaily and, in some, even higher. Typical doses used rangefrom 500 milligrams to 2 grams daily. Some increa~e theirdose to 4 to 5 grams daily when coming down with a cold.Such doses may have antihistaminic-like action. A dose ofvitamin C of 5 grams daily for 4 weeks was found tosignificantly inhibit Helicobacter pylori in one report.Although a dose of 200 milligrams daily is almost enough tomaximize plasma and lymphocyte levels, high doses may aidin detoxifying some carcinogens in the stomach prior toabsorption of the vitamin.

Absorption of supplemental vitamin C is most efficient ifspaced throughout the day or if taken in time-release form.

T~e DV (Daily Value) for vitamin C, which is used fordetermining percentage of nutrient daily values on nutritionalsupplement and food labels, is 60 mg. This is based on theU.S. RDA for vitamin C.

In the United States, the average intake of vitamin C is about95 milligrams for women and 107 milligrams for men.Children between the ages of one to five consume about 83milligrams daily.

The most rece~t (2,000) dietary reference intakes (DRI) forvitamin C are as follows:

666/VITAMIN C

Infants Adequate Intake Tolerable Upper In-(AI) take Level (UL)

0-6 months 40 milligrams NDdaily or 6mglkg

7-12 months 50 milligrams NDdaily or 6mglkg

Recommended Tolerable UpperDietary Intake Level (UL)Allowances

Children (RDA)1-3 years 15 mg daily 400 mg daily4-8 years 25 mg daily 650 mg daily

Boys9-13 years 45 mg daily 1,200 mg daily14-18 years 75 mg daily 1,800 mg daily

Girls9-13 years 45 mg daily . 1,200 mg daily14-18 years 65 mg daily 1,800 mg daily

Men19-30 years 90 mg daily 2,000 mg daily31-50 years 90 mg daily 2,000 mg daily51-70 years 90 mg daily 2,000 mg dailyOlder than 70 90 mg daily 2,000 mg dailyyears

Women19-30 years 75 mg daily 2,000 mg daily31-50 years 75 mg daily 2,000 mg daily51-70 years 75 mg daily 2,000 mg dailyOlder than 70 75 mg daily 2,000 mg dailyyears

Pregnancy14-18 years 80 mg daily 1,800 mg daily19-30 years 85 mg daily 2,000 mg daily31-50 years 85 mg daily 2,000 mg daily

Lactation14-18 years 115 mg daily 1,800 mg daily19-30 years 120 mg daily 2,000 mg daily31-50 years 120 mg daily 2,000 mg daily

SmokersMen 125 mg daily NRWomen 110 mg daily NR

ND = Not determinableNR = Not reported

A LOAEL (Lowest-Observed-Adverse-Effect Level) of 3grams daily has been established for vitamin C for adults.Based on this LOAEL, a Tolerable Upper Level Intake (UL)

PDR FOR NUTRITIONAL SUPPLEMENTS

for the vitamin has been set at 2 grams daily for men andwomen 19 years and older.

LITERATURE

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Audera C, Patulny RV, Sander BH, et al. Mega-dose vitamin Cin treatment of the common cold: a randomised controlled trial.Med J Aust. 2001;175(7):359-362.

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Cooke MS, Evans MD, Podmore ro, et al. Novel repair actionof vitamin C upon in vivo oxidative DNA damage. FEBS Left.1998;439:363-367.

Douglas RM, Hemilii H, Chalker E, et al. Vitamin C forpreventing and treating the common cold. Cochrane DatabaseSyst Rev. 2007;(3):CD000980.

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Enstrom JE, Kanim LE, Klein MA. Vitamin C intake andmortality among a sample of the United States population.Epidemiology. 1992;3: 194-202.

Fan X, Monnier VM. Vitamin C-mediated Maillard reaction inthe lens probed in a transgenic-mouse model. Ann N Y AcadSci. 2008;1126:194-200.

Fan X, Reneker LW, Obrenovich ME, et al. Vitamin Cmediates chemical aging of lens crystallins by the Maillardreaction in a humanized mouse model. Proc Natl Acad SciUSA. 2006;103(45):16912-16917.

Fay MJ, Bush MJ, Verlangieri AJ. Effect of aldonic acids onthe uptake of ascorbic acid by 3T3 mouse fibroblasts andhuman T lymphoma cells. Gen Pharmacol. 1994;25: 1465-1469.

Fay MJ, Verlangieri AJ. Stimulatory action of calcium L-threonate on ascorbic acid uptake by a human T-Iymphoma cellline. Life Sci. 1991;49:1377-1381.

Fischer H, Schwarzer C, IIIek B. Vitamin C controls the cysticfibrosis transmembrane conductance regulator chloride channel.Proc Natl Acad Sci USA. 2004;101(10):3691-3696.

Frei B, Lawson S.Vitamin C and cancer revisited. Proc NatlAcad Sci USA. 2008;105(32):11037-11038.

Friedman PA, Zeidel ML. Victory at C. Nature Med.1999;5:620-62 I.

Gamble J, Grewal PS, Gartside lB. Vitamin C modifies thecardiovascular and microvascular responses to cigarette smokeinhalation in man. Clin Science. 2000;98:455-460.

Giovannoni 11. Completing a pathway to plant vitamin Csynthesis. Proc Natl Acad Sci USA. 2007;104(22):9109-9110.

Gomez-Cabrera MC, Domenech E, Romagnoli M, et al. Oraladministration of vitamin C decreases muscle mitochondrialbiogenesis and hampers training-induced adaptations inendurance performance. Am J Clin Nutr. 2008;87(1):142-149.

Gonzalez JP, Valdivieso A, Calvo R, et al. Influence of vitaminC on the absorption and first pass metabolism of propranolol.Eur J Clin Pharmacol. 1995;48(3-4):295-297.

Grad JM, Bahlis NJ, Reis I, et al. Ascorbic acid enhancesarsenic trioxide-induced cytotoxicity in multiple myeloma cells.Blood. 200 I;98(3):805-813.

Halliwell B. Vitamin C: poison, prophylactic or panacea?Trends Biochem Sci. 1999;24:255-259.

Harakeh S, Jariwalla RJ, Pauling L. Suppression of humanimmunodeficiency virus replication by ascorbate in chronicallyand acutely infected cells. Proc Natl Acad SciUSA.1990;87:7245-7249.

Harding AH, Wareham NJ, Bingham SA, et al. Plasma vitaminC level, fruit and vegetable consumption, and the risk of new-onset type 2 diabetes mellitus: the European prospective

investigation of cancer-Norfolk prospective study. Arch InternMed. 2008;168(14):1493-1499.

Harding 11, Hassett PC, Rixon KC, et al. Sugars includingerythronic and threonic acids in the human aqueous humor.Curr Eye Res. 1999; 19:131-136.

Heaney ML, Gardner JR, Karasavvas N, et al. Vitamin CAntagonizes the Cytotoxic Effects of Antineoplastic Drugs.Cancer Research. 2008;68:8031-8038.

Hemilii H, Douglas RM. Vitamin C and acute respiratoryinfections. Int J Tuberc Lung Dis. 1999;3:756-76 I.

Hemilii H, Koivula TT. Vitamin C for preventing and treatingtetanus. Cochrane Database Syst Rev. 2008;(2):CD006665.

Hemilii H, Louhiala P. Vitamin C for preventing and treatingpneumonia. Cochrane Database Syst Rev. 2007;(I):CD005532.

Hodison T, Socaciu C, Ropan I, et al. Carotenoid compositionof Rosa canina fruits determined by thin-layer chromatographyand high performance liquid chromatography. J PharmaceutBiomed Anal. 1997; 16:521-528.

Hornero-Mendez D, Minguez-Mosquera MI. Carotenoidpigments in Rosa mosqueta hips, an alternative carotenoidsource for foods. J Agric Food Chem. 2000;48:825-828.

Hwang J, Peterson H, Hodis HN, et al. Ascorbic acid enhances17 beta-estradiol-mediated inhibition of oxidized low densitylipoprotein formation. Atherosclerosis. 2000; 150:275-284.

Institute of Medicine, Food and Nutrition Board. DietaryReference Intakes for vitamin C, vitamin E, Selenium, andCarotenoids. Washington, DC: National Academy Press, 2000.

Ip C. Interaction of vitamin C and selenium supplementation in

the modification of mammary carcinogenesis in rats. J NatCancer Inst. 1986;77:299-303.

Jacob RA. Vitamin C In: Shils ME, Olson JA, Shike M, RossAC, eds. Modem Nutrition in Health and Disease. 9th ed.Baltimore, MD: William and Wilkins; 1999:467-483.

Jarosz M, Dzieniszewski J, Dabrowska-Ufniarz E, et al. Effectsof high dose vitamin C treatment on Helicobacter pyloriingestion and total vitamin C concentration in gastric juice. EurJ Cancer Prevo 1998;7:449-454.

Kelly RP, Poo Yeo K, Isaac HB, et al. Lack of effect of acuteoral ingestion of vitamin C on oxidative stress, arterial stiffnessor blood pressure in healthy subjects. Free Radic Res.2008;42(5):514-522.

Koc M, Imik H, Odabasoglu F. Gastroprotective and Anti-oxidative Properties of Ascorbic Acid on Indomethacin-inducedGastric Injuries in Rats. Bioi Trace Elem Res. Epub: 2008 Aug23.

Kurbacher CM, Wagner U, Kolster B, et al. Ascorbic acid(vitamin C) improves the antineoplastic activity of doxorubicin,cisplatin, and paclitaxel in human breast carcinoma cells invitro. Cancer Letters. 1996; 103:183-189.

Kwaselow A, Rowe M, Sears-Ewald'D, Ownby D. Rose hips: anew occupational allergen., J Allergy Clin Immunol.1990;85:704-708.

730/YOGURT PDR FOR NUTRITIONAL SUPPLEMENTS

tolerated by those with lactase-deficiency than nonfermented

milk.

ADVERSE REACTIONS

There are some reports of flatulence and diarrhea in somewith lactase-deficiency.

OVERDOSAGE

None known.


Yogurt is available in many different preparations. Yogurtmay be considered a functional food. In some yogurtpreparations, the lactic acid bacteria have been killed duringthe processing of the product via pasteurization. Yogurtpreparations in which the lactic acid bacteria have beenkilled may still confer some, but probably not all, of thepossible health benefits.

Intake of yogurt is variable. One study showing a possibleanti-allergy effect of yogurt used 200 grams daily for oneyear. Unpasteurized yogurt was found to be more effectivethan pasteurized yogurt in this study.

LITERATURE

Bertolami MC, Faludi AA, Batlouni M. Evaluation of theeffects of a new fermented milk product (G91O)on primaryhypercholesterolemia. Eur J C/in Nutr. 1999; 53:97-101.

Danielson AD, Peo ER Jr, Shahani KM, et al.Anticholesterolemic property of Lactobacillus acidophilus yogurtfed to mature boars. J Anim Sci. 1989; 67:966-974.

Hepner G, Fried R, St Jeor S, et al. Hypocholesterolemic effectof yogurt and milk. Am J Clin Nutr. 1979; 32: 19-24.

Hitchins AD, McDonough FE. Prophylactic and therapeuticaspects of fermented milk. Am J Clin Nutr. 1989; 49:675-684.

Kolars JC, Levitt MD, Aouji M, Savaiano DA. Yogurt-anautodigesting source of lactose. N Engl J Med. 1984; 310: 1-3.

Mann GV. A factor in yogurt which lowers cholesterolemia inman. Atherosclerosis. 1977; 28:335-340.

Metchnikoff E. The Prolongation of Life: Optimistic Studies.The English translation. Mitchell PC, ed. 1908; GP Putnam'sSons: New York.

Meydani SN, Ha W-K. Immunologic effects of yogurt. Am C/inNutr. 2000; 71:861-872.

Van de Water J, Keen CL, Gershwin ME. The influence ofchronic yogurt consumption on immunity. J Nutr. 1999;129:1492S-1495S.

ZincDESCRIPTION

Zinc is an essential element in human and animal nutritionwith a wide range of biological roles. Zinc plays catalytic,

structural or regulatory roles in the more than 200 zincmetalloenzymes that have been identified in biologicalsystems. These enzymes are involved in nucleic acid andprotein metabolism and the production of energy, amongother things. Zinc plays a structural role in the formation ofthe so-called zinc fingers. Zinc fingers are exploited bytranscription factors for interacting with DNA and regulatingthe activity of genes. Another structural role of zinc is in themaintenance of the integrity of biological membranesresulting in their protection against oxidative injury, amongother things.

Zinc is a metallic element with atomic number 30 and anatomic weight of 65.37 daltons. Its atomic symbol is Zn.Zinc exists under physiological conditions in the divalentstate. The adult body contains about 1.5 to 2.5 grams of zinc.It is present in all organs, tissues, fluids and secretions.Approximately 90% of total body zinc is found in skeletalmuscle and bone. Over 95% of total body zinc is bound toproteins within cells and cell membranes. Plasma containsonly 0.1% of total body zinc. Most of the zinc (75% to 88%)in blood is found in the red blood cell zinc metalloenzymecarbonic anhydrase. In the plasma, approximately 18% ofzinc is bound to alpha-2-macroglobulin, 80% to albumin and2% to such proteins as transferrin and ceruloplasmin.

Physiologically, zinc is vital for growth and development,sexual maturation and reproduction, dark vision adaptation,olfactory and gustatory activity, insulin storage and releaseand for a variety of host immune defenses, among otherthings. Zinc deficiency can result in growth retardation,immune dysfunction, increased incidence of infections,hypogonadism, oligospermia, anorexia, diarrhea, weightloss, delayed wound healing, neural tube defects of the fetus,increased risk .for abortion, alopecia, mental lethargy andskin changes. I

Moderate to severe zinc deficiency is rare in industrializedcountries. However, it is highly prevalent in developingcount~es. Many, however, are at risk for mild zinc deficien-cy in !ndustrialized countries. Several diseases and situationspredispose to zinc deficiency, including the autosomalrecessive disease acrodermatitis enteropathica, alcoholism,malabsorption, thermal burns, total parenteral nutrition(TPN) without zinc supplementation and certain drugs, suchas diuretics, penicillamine, sodium valproate and ethambutol.Zinc intake in many of the elderly may be suboptimal and, ifcompounded with certain drugs and diseases, can lead tomild or even moderate zinc deficiency.

Zinc acetate is an 'FDA-approved orphan drug for thetreatment of the copper-overload disorder Wilson's disease.

SUPPLEMENT MONOGRAPHS ZINC /731


ACTIONS

Zinc may have immunomodulatory activity. It may also haveantioxidant activity. Zinc has putative antiviral, fertility-enhancing and retinoprotective activities.

MECHANISM OF ACTION

Zinc is required for a number of immune functions,including T-lymphocyte activity. Zinc deficiency results inthymic involution, depressed delayed hypersensitivity, de-creased peripheral T-lymphocyte count, decreased prolifera-tive T-lymphocyte response to phytohemagglutinin (PHA),decreased cytotoxic T-lymphocyte activity, depressed Thelper lymphocyte function, depressed natural killer cellactivity, depressed macrophage function (phagocytosis),depressed neutrophil functions (respiratory burst, chemo-taxis) and depressed antibody production. Zinc supplementa-tion can restore impaired immune function in those with zincdeficiency, as found in malabsorption syndromes andacrodermatitis enteropathica.

There is little evidence that zinc supplementation willenhance immune responses in those who are not zincdeficient. High doses of zinc may even be immunosuppres-sive. Zinc supplementation may improve immune function inhealthy elderly individuals who are marginally zincdeficient.

The mechanism underlying the immune effects of zinc is notfully understood. Some of these effects may be accounted forby zinc's membrane-stabilization effect. This could affectsignaling processes involved in cell-mediated immunity.Zinc is known to be involved in such signaling processes.Zinc may also influence gene expression by structuralstabilization of different immunological transcription factors.Zinc ions can induce blast formation of human peripheralblood monocytes (PBMCs). In PBMCs, zinc induces cyto-kines, including interleukin (IL)-I, IL-6 and tumor necrosisfactor (TNF)-alpha. Cytokine induction by zinc is caused bya direct interaction of zinc with monocytes. The stimulationby zinc of T-lymphocytes appears to occur via monocytereleased IL-l and cell-cell contact. High.zinc concentrationsinhibit T-Iymphocyte proliferation by blocking the IL-l typeI receptor-associated kinase. T-lymphocyte activation ap-pears to be delicately regulated by zinc concentrations.

Zinc may have secondary antioxidant activity. Zinc does nothave redox activity under physiological conditions. Zinc mayinfluence membrane structure by its ability to stabilize thiolgroups and phospholipids. It may also occupy sites thatmight otherwise contain redox active metals such as iron.These effects may protect membranes against oxidativedamage. Zinc also comprises the structure of copper/zinc-superoxide dismutase (CulZn-SOD). Zinc plays a structural

role in CulZn-SOD. Zinc may also have antioxidant activityvia its association with the copper-binding proteinmetallothionein.

The role of zinc gluconate in the management of thecomrnoncold remains controversial (see Research Summa-ry). The mechanisms proposed for zinc's effects on theduration of colds are inhibition by zinc of the replication ofrhinoviruses and/or inhibition of virus entry into cells. Zincions, however, have only modest nonselective inhibitoryeffects for rhinoviruses in vitro.

Zinc is involved in sperm formation and testosteronemetabolism. Zinc deficiency results in oligospermia. There islittle evidence that zinc supplementation affects spermproduction in those who are not zinc deficient.

the mechanism of the putative effect of zinc in age-relatedmacular degeneration (ARMD) is unknown.

PHARMACOKINETICS

The efficiency of absorption (fractional absorption) of a zincsalt on an empty stomach ranges from 40% to 90%. Thefractional absorption of zinc with food appears to be lower.Zinc-histidine, zinc-methionine and zinc-cysteine complexesappear to be more efficiently absorbed than other zincsupplementary forms. Zinc is absorbed all along the smallintestine. Most ingested zinc appears to be absorbed from thejejunum. Zinc uptake across the brush border appears tooccur by both a saturable barrier-mediated mechanism and anonsaturablenonmediated mechanism. The exact mechanismof zinc transport into the enterocytes remains unclear. Zinctransporters have been identified in animal models. Oncezinc is within the enterocyte, it can be used for zinc-dependent processes, become bound to metallothionein andheld within the enterocyte or pass through the cell. Transportof zinc across the serosal membrane is carrier mediated andenergy dependent.

Zinc is transported to the liver via the portal circulation. Afraction of zinc is extracted by the hepatocytes, and theremaining zinc is transported to the various cells of the bodyvia the systemic circulation. Zinc is transported in the plasmabound to albumin (about 80%), alpha-2-macroglobulin(about 18%) and to such proteins as transferrin andceruloplasmin (about 2%). The major route of zinc excretionis via the gastrointestinal tract. Fecal zinc excretion iscomprised of unabsorbed zinc and zinc derived from biliary,pancreatic, and gastrointestinal secretions and zinc fromsloughing of mucosal cells.

Much of the pharmacokinetics of ZInC in humans IS

unknown. Research is ongoing.

732/ZINC PDR FOR NUTRITIONAL SUPPLEMENTS


Even borderline zinc deficiency or disturbances in zincmetabolism can have profound adverse health effects. Thoseat greatest risk of such deficiencies and disturbances includeinfants, children, the elderly and pregnant women. Due toconditions that can limit the bioavailability of zinc, evenwhen there is adequate zinc intake, zinc deficiency mayaffect still larger populations.

Among diseases and conditions associated with zinc defi-ciency are alcoholism, malabsorption syndromes, acroderma-titis enteropathica, anorexia nervosa, thermal bums and totalparenteral nutrition (TPN) without zinc supplementation.Supplemental zinc may be helpful in some of the foregoing,in some conditions of immune impairment, in some compli-cations of pregnancy, in the prevention of some c~ses of fetalneural tube defects, diarrhea, oligospermia, delayed woundhealing and some cognitive disorders. It may also helpprotect against some inflammatory conditions.

Some claim that zinc is neuroprotective, others that it isneurotoxic in some circumstances. Some have suggested itmight be useful in depression, and some others haveproposed that it might be used as an antiaging substance.Mixed results are reported in the use of zinc in childhoodpneumonia.

Widely publicized claims that zinc is efficacious in prevent-ing and ameliorating symptoms of the common cold aresupported by some studies but not by others. There is thesuggestion in some experimental research that zinc mighthave some anticarcinogenic effects. There is little evidencethat zinc is helpful in diabetes. Topical zinc is useful intreating some skin conditions. Claims that it can prevent orreverse baldness are unsubstantiated except in some cases ofsevere zinc deficiency. It has no effect on typical malepattern baldness. It may be useful in dysgeusia (tastedisorder) in those who are zinc deficient. There is growingevidence that zinc might be helpful in preventing age-relatedmacular degeneration.

RESEARCH SUMMARY

Zinc deficiency has been shown to impair immunity in manyways. It decreases T- and B-Iymphocyte function anddiminishes proliferative responses to mitogens. It alsoreduces the biological activity of many cytokines. Zincdeficiency has been shown to impair placental transport ofantibodies from mother to fetus. Even mild zinc deficiencyhas been shown to produce an imbalance between cell-mediated and humoral immunity. Zinc supplementation hasreversed many of these and other immune deficits in severalin vitro, animal and human studies.

Supplementation with zinc reduced the incidence of child-hood pneumonia by 41% and incidence of diarrhea in

children by 25%, according to the findings of a review of tenrandomized, controlled studies in the developing world. Zincwas found, in this review analysis, to be more effective thanany other treatment for childhood pneumonia and was said toequal most other effective interventives for diarrhea in thesepopulations. The diarrheas studied were related to dimin-ished immune competence and high rates of exposure toinfectious diseases. The significance of these findings isunderscored by the fact that respiratory infections, andpneumonia in particular, are the cause of approximately one-third of all deaths among children in developing countries.

Many healthy elderly individuals and even more unhealthyelderly have marginal zinc deficiencies. There is bothclinical and experimental evidence of impaired T-Iympho-cyte function, with associated increases in morbidity andmortality due to infectious' diseases, among the elderly. Zincdeficiency has been shown to play a key role in thissituation. Zinc supplementation in the elderly has producedmixed results with respect to immune restoration. Manyresearchers agree, however, that some of the negative resultsare probably due to the heterogeneity of elderly populationswith respect to immune response, and most call for better-designed studies to bring hitherto ambiguous data intosharper focus.

Disturbances in metabolism, as well as zinc deficiency, havebeen associated with some inflammatory conditions, includ-ing some inflammatory bowel diseases and rheumatoidarthritis. The use of supplemental zinc in gastrointestinalinflammation, however, is highly experimental and is notwithout peril since inappropriate or uncontrolled administra-tion can exacerbate, rather than ameliorate, some of theseconditions. In some circumstances, however, supplementalzinc has enhanced the mucosal capacity of the small bowelto absorb water and electrolytes, thus easing inflammation.There is also some experimental evidence that zinc canstimulate tissue repair in some ulcer conditions.

There is some preliminary clinical evidence that supplemen-tal zinc can produce benefit in some with rheumatoidarthritis. Diminished plasma zinc has been reported in somewith this disease. Zinc has demonstrated an ability to inhibitmixed lymphocyte reaction in some of these subjects. Someresearchers have suggested that further research is warrantedto see if zinc might be a useful new therapy in T-cell-mediated auto-immune and graft-versus-host diseases.

One review author has presented evidence that zinc can beneurotoxic in some experimental circumstances and neuro-protective in others. The author warned that "there is a largeand growing body of evidence showing that after CNSinjury, large quantities of free zinc can be released, not justfrom pre-synaptic vesicles but also from metalloproteins and

SUPPLEMENT MONOGRAPHS ZINC /733

from mitochondrial zinc pools, resulting in neuronal damageand death." Some in vitro work has shown neurotoxic zinceffects, and some in vivo studies have shown free zincaccumulation reportedly leading directly to neuronal deathafter ischemia, traumatic brain injury and seizure. And thereis some, albeit inconsistent, data suggesting that zincchelators may protect neurons after injury. At the same time,there is data indicating that following traumatic brain injury,the risk for moderate-to-severe zinc deficiency increasessignificantly in humans. Hence the reviewer stated that"while these data make it clear that systemic zinc deficiencyafter CNS injury should be avoided, our understanding of therole of free zinc in neuronal death raises the question ofwhether clinicians should be treating brain-injured patientswith supplemental zinc."

This issue was tested in a rat model of traumatic brain injury.Dietary supplementation with zinc subsequent to the inducedbrain trauma did not have deleterious effects, but theresearchers cautioned that in patients with severe traumaticbrain injury zinc supplementation would necessarily beadministered parenterally with, potentially, significantlydifferent effects. Another study provided at least somereassurance in this context: brain injured human adultsreceived intravenous zinc for 15 days beginning within 72hours of injury; three weeks after treatment began no adverseeffects were observed, and, in fact, within two weeks afterinjury, those receiving zinc compared to those who did notreceive it had improved recovery scores on the GlasgowComa Scale. In another study, however, zinc chlorideadministered intraperitoneally 30 minutes prior to emboliza-tion of the middle cerebral artery in adult male rats resultedin increased infarct size and diminished behavioral out-comes, compared with other agents tested. Both studies usedthe same zinc form and dose. But the methods used to inducetransient ischemia and reperfusion were different. Clearlymore research needs to be done to try to further clarify theissues raised in these conflicting studies.

A group of reviewers examined data they said might indicatea role for zinc in treating depression. They presentedevidence indicating that zinc deprivation influences brainhomeostasis, mental function and susceptibility to epilepticconvulsions. They also pointed to recent rat studies showingthat chronic treatment with antidepressants and electrocon-vulsive shock therapy induces increased brain concentrationsof zinc. Zinc supplementation has produced antidepressant-like effects in various animal depression'models. The activityof some antidepressants was said to be enhanced when usedin combination with zinc. There have been some reports thatdepression in humans is associated with lower serum zincconcentrations. At least one such inquiry, however, failed tofind such an association. A preliminary clinical trial found

some benefit from zinc supplementation in depressed indi-viduals. More research is needed and warranted.

Another group of researchers, surveying a broad range ofzinc data, recently concluded that zinc may have generalantiaging . properties: "An overall estimation of all experi-mental and clinical observations on the biological role ofzinc seem~ to lead us to the conclusion that zinc supply maybe useful in reducing infection relapse and in restoringimmune efficiency in ageing and in preventing age-relateddegenerative disease." However, they cautioned that it is farfrom being the ideal antiaging substance since there is alsothe potential for "acute and chronic zinc poisoning."

Diminished zinc status has been associated with HIV diseaseand higher incidence of opportunistic infections. Zinc

\

supplementation has produced higher CD4+ lymphocyte cellcounts and reduced incidence of bacterial infections amongpatients with HIV disease in one study.

In a double-blind study, subjects were randomized to receivezinc lozenges containing 13.3 milligrams of zinc every twohours while awake for as long as they had symptoms of thecommon cold. Subjects were enrolled within 24 hours of firstreporting cold symptoms. Median time to complete resolu-tion of cold symptoms was 4.4 days in those supplementedwith zinc, compared with 7.6 days in those receivingplacebo. Patients dissolved the lozenges in their mouths,rather than immediately swallowing them.

A recent review of studies found findings similar to thosereported above in three additional studies. Four other studies,however, found no benefit from zinc in shortening durationof cold symptoms. In one of the other positive studies, zincsupplementation reduced duration of symptoms by 42%,compared with placebo, when initiated on the first day ofsymptoms. When withheld until the second day, zincreduced cold duration' by 26%, compared with placebo.

Some have challenged the validity of the four studies thatfound no zinc effect on the basis of poor bioavailability ofthe zinc lozenge preparations, either due to a proposedfailure of the lozenge formulations to provide adequateamounts of free zinc ions to the saliva and oral tissues or dueto doses of zinc in the lozenge that were below a possibletherapeutic threshold. On the other hand, some have alsoargued that there were significant methodological flaws insome of the positive studies. A recent review of the zinc/colddata evaluated 14 randomized, placebo-controlled studies.Half reported positive effects; half reported no effect. Of thefour studies the review authors considered the most rigorousand best-designed, three found no effect, and one reported apositive effect-but it used a nasal gel as the delivery form.Whether zinc is truly effective against colds remains anunresolved issue.

734/ZINC PDR FOR NUTRITIONAL SUPPLEMENTS

A group of researchers has recently concluded that supple-mental zinc has been shown to reduce the incidence ofchildhood pneumonia. Some studies in which it has beenused as an adjunct to antibiotic therapy have yielded mixedresults. A recent trial suggested that supplemental zinc mightactually be detrimental in some cases of childhood pneumo-nia. Again, the picture is unclear, and more research isrequired.

Zinc supplementation has reversed some of the signs ofanorexia nervosa, including weight loss, in some women.Weight has increased in some zinc-supplemented womenwith this condition, and menstruation has been restored insome supplemented with zinc.

Zinc supplementation has overcome some forms of bothfemale and male infertility in those who are zinc deficient.Zinc is essential for proper formation and maturation ofspermatozoa.

Zinc plays many roles in pregnancy, and disturbances in zincmetabolism, as well as zinc deficiency, can have seriousadverse effects on the course of pregnancy and upon thegrowth of the fetus and newborn. Zinc deficiency can beteratogenic, producing neural tube defects. Zinc is also veryimportant to the newborn when breast milk may be its onlysource of zinc (during the first few months of life).Premature infants may be at even greater risk of zincdeficiency. Impaired disease resistance and diminishedvaccine efficacy in infants may result from zinc deficiency atthis stage. Some studies have shown that giving 15milligrams of zinc daily to breast-feeding mothers producedmore weight gain in their babies than in the babies ofunsupplemented mothers. Zinc supplementation in infantsnot breast fed has also shown benefits. Zinc supplementationhas also shown benefit in regulating and promoting propergrowth in some groups of young children with non-organicfailure to thrive.

There is some evidence that zinc can promote and acceleratewound healing in some circumstances. There is verypreliminary experimental evidence that it may have someprotective effects against prostate cancer and some equallypreliminary data suggesting that it might enhance neuropsy-chological performance in children, most likely those withzinc deficiencies.

There was an early report that 100 milligrams of zinc twice aday with meals significantly reduced visual loss in subjects

with macular degeneration. Subsequently, in a much largerstudy organized by the National Eye Institute, a combinationof zinc, vitamin E, beta-carotene and vitamin C reportedlyreduced the risk of developing age-related macular degener-ation and prevented blindness in a high-risk group of elderly

subjects. Mortality was also increased in the supplementedgroup.


CONTRA INDICA TlONS

Zinc is contraindicated in those who are hypersensitive toany component of a zinc-containing supplement.

PRECAUTIONS

Pregnant women and nursing mothers should avoid zinc

doses higher than RDA amounts (I5 milligrams/day forpregnant women, 19 mg/day for lactating women during the

first six months and 16 mg/day for lactating women duringthe second six months).

ADVERSE REACTIONS

Doses of zinc up to 30 milligrams daily are generally welltolerated. Higher doses may cause adverse reactions. The

most common adverse reactions are gastrointestinal andinclude nausea, vomiting and gastrointestinal discomfort.Other adverse reactions include a metallic taste, headache

and drowsiness. There are some reports of decreased HDL-cholesterol in those taking high doses of zinc. Chronic intakeof high doses of zinc can lead to copper deficiency andhypochromic, microcytic anemia secondary to zinc-inducedcopper deficiency.

High doses of zinc may be immunosuppressive.

INTERACTIONS

DRUGS

Bisphosphonates (alendronate. etidronate. risedronate):

Concomitant intake of a bisphosphonate and zinc maydecrease the absorption of both the bisphosphonate and zinc.

Quinolones (ciprojloxacin. gatifloxacin. levojloxacin. lome-

jloxacin. moxifloxacin. norjloxacin. ojloxacin. sparjloxacin.

trovajloxacin): Concomitant intake of a quinolone and zincmay decrease the absorption of both the quinolone and zinc.

Penicillamine: Concomitant intake of penicillamine and zincmay depress absorption of zinc.

Tetracyclines (doxycycline. monocycline. tetracycline): Con-

comitant intake of a tetracycline and zinc may decrease theabsorption of both the tetracycline and zinc.


Calcium: Concomitant intake of calcium and zinc maydepress zinc absorption in postmenopausal women.

Copper: Concomitant intake of copper and zinc may depress

the absorption of copper. Intake of large doses of zinc cannegatively affect the copper status of the body. This is thebasis for the use of high doses of zinc for the treatment ofWilson's disease. It is thought that high intakes of zincinduce synthesis of the copper-binding protein metallothio-

ZINC 1735

Recommended DailyAllowance (RDA)

0-6 months 2 mg/day (AI, adequateintake)

7-12 months 3 mg/day

Children Recommended DailyAllowance (RDA)

1-3 years 3 mg/day4-8 years 5 mg/day

Boys9-13..years 8 mg/day14-18 years II mg/day

Girls9-13 years 8 mg/day14-18 years 9 mg/day

Men19-30 years 11 mg/day31-50 years 11 mg/day51-70 years II mg/dayOlder than 70 years 11 mg/day

Women19-30 years 8 mg/day31-50 years 8 mg/day51-70 years 8 mg/dayOlder than 70 years 8 mg/day

Pregnancy14-18 years 12 mg/day19-30 years II mg/day31-50 years 11 mg/day

Lactation14-18 years 13 mg/day19-30 years 12 mg/day31-50 years 12 mg/day

SUPPLEMENT MONOGRAPHS

nine in the gastrointestinal mucosal cells. Metallothioninecan sequester copper. This makes copper unavailable forcopper absorption.

L-cysteine: Concomitant intake of L-cysteine and zinc mayenhance the absorption of zinc.

L-histidine: Concomitant intake of L-histidine and zinc mayenhance the absorption of zinc.

Inositol Hexaphosphate: Concomitant intake of inositolhexaphosphate and zinc may depress the absorption of zinc.

Iron: Concomitant intake of iron and zinc may depress theabsorption of both iron and zinc.

L-methionine: Concomitant intake of L-methionine and zincmay enhance the absorption of zinc.

N-acetyl-L-cysteine (NAC): Concomitant intake of NAC andzinc may enhance the absorption of zinc.

Phosphate Salts: Concomitant administration of zinc andphosphate salts may decrease the absorption of zinc.

FOODSCaffeine: Concomitant intake of coffee, caffeinated bever-ages or caffeine and zinc may depress the absorption of zinc.

Cysteine-containing Proteins: Foods rich in cysteine-con-taining proteins (e.g., animal muscle tissue) may increase theabsorption of zinc if ingested concomitantly.

Oxalic Acid: Concomitant intake of zinc with foods rich inoxalic acid (spinach, sweet potatoes, rhubarb and beans) maydepress the absorption of zinc.

Phytic Acid: Concomitant intake of zinc with foods rich inphytic acid (unleavened bread, raw beans, seeds, nuts andgrains and soy isolates) may depress the absorption of zinc.

Tea: Concomitant intake of tea (tannins) and zinc may causedecreased absorption of zinc.

OVERDOSAGE

There are no reports of overdosage from use of zincsupplements.


There are several zinc supplementary forms. These includezinc gluconate, zinc oxide, zinc aspartate, zinc picolinate,zinc citrate, zinc monomethionine and zinc histidine. Zincsupplements are available in stand-alone or in combinationproducts. A typical dose of zinc is about 15 milligrams (aselemental zinc) daily.

The Food and Nutrition Board of the Institute of Medicine ofthe National Academy of Sciences has recommended thefollowing Dietary Reference Intakes (DRI) for zinc:

The following summarizes the Tolerable Upper Intake Level(UL) for various age groups and conditions:

Infants0-6 months7-12 months

4 mg/day5 mg/day

(UL)7 mg/day

12 mg/day23 mg/day

Children1-3 years4-8 years9-13 years

Adolescents14-18 years 34 mg/day

736 I ZINC PDR FOR NUTRITIONAL SUPPLEMENTS

Adults

19 years and older

Pregnancy14-18 years19 years and older

40 mg/day

34 mg/day40 mg/day

Lactation14-18 years19 years and older

34 mg/day40 mg/day

The DV (Daily Value) for zinc, which is used for determin-ing percentage of nutrient daily values on nutritionalsupplement and food labels, is 15 mg. The basis for the DVfor zinc is the 1973 U.S. RDA.

LITERATURE

Anon. Zinc lozenges reduce cold symptoms. Nutr Rev.1997;55:82-88.

Arnold LE, DiSilvestro RA. Zinc in attention-deficitlhyperactivitydisorder. J Child Adolesc Psychopharmacol.2005; 15(4):619-627.

Beletate V, EI Dib RP, Atallah AN. Zinc supplementation forthe prevention of type 2 diabetes mellitus. Cochrane DatabaseSyst Rev. 2007;(1):CD005525.

Berg JM, Shi Y. The galvanization of biology: a growingappreciation for the roles of zinc. Science. 1996;271:1081-1085.

Bhutta ZA, Black RE, Brown KH, et al. Prevention of diarrheaand pneumonia by zinc supplementation in children indeveloping countries: Pooled analysis of randomized controlled .

trials. J Pediatr. 1999;135:689-697.

Caruso TJ, Prober CG, Gwaltney JM Jr. Treatment of naturallyacquired common colds with zinc: a structured review. ClinInfect Dis. 2007;45(5):569-574.

Chandra RK. Excessive intake of zinc impairs immuneresponse. JAMA. 1984;252: 1443-1446.

Cuajungco MP, Lees GJ. Zinc metabolism in the brain;relevance to human neurodegenerativedisorders. Neurobiol Dis.1997;4:137-169.

Cuevas LE, Koyanagi A. Zinc and infection: a review. AnnTrop Paediatr. 2005;25(3): 149-160.

Duchateau J, Delepesse G, Vrijens R, et al. Beneficial effectsof oral zinc duration on the immune response of old people.Am J Med. 1981;70:1001-1004.

Fabris N, Mocchegiani E. Zinc, human diseases and aging.Aging Clin Exp Res. 1995;7:77-93.

Fong LY, Zhang L, Jiang Y, et al. Dietary zinc modulation ofCOX-2 expression and lingual and esophageal carcinogenesis inrats. J Natl Cancer Inst. 2005;97(1):40-50.

Grahn BH, Paterson PG, Gottschall-Pass KT, et al. Zinc andthe eye. J Am Coli Nutr. 200 I;20(2 Suppl): 106-118.

Griingreiff K, Griingreiff S, Reinhold D. Zinc deficiency andhepatic encephalopathy: results of a long-term follow-up on zincsupplementation.J Trace Elem Exp Med. 2000;13:21-31.

HambridgeM. Human zinc deficiency.J Nutr. 2000;130:I344S-1349S.

Herbein G, Varin A, Fulop T. NF-kappaB, AP-I, Zinc-deficiency and aging. Biogerontology. 2006;7(5-6):409-419.

Heyland DK, Jones N, Cvijanovich NZ, et al. Zincsupplementation in critically ill patients: a keypharmaconutrient?'JPENJ Parenter Enteral Nutr.2008;32(5):509-519.

Hughes S, Samman ,So The effect of zinc supplementation inhumans on plasma lipids, antioxidant status and thrombogenesis.J Am Coli Nutr. 2006;25(4):285-291.

Hulisz D. Efficacy of zinc against common cold viruses: anoverview.J Am Pharm Assoc (2003). 2004;44(5):594-603.

Institute of Medicine, Food and Nutrition Board. DietaryReference Intakes for vitamin A, vitamin K, arsenic, boron,chromium, copper, iodine, iron, manganese, molybdenum,nickel, silicon, vanadium, and zinc. Washington, DC: NationalAcademy Press, 2001.

Jackson JL, Peterson C, Lesho E. A meta-analysis of zinc salts,lozenges and the common cold. Arch Intern Med.1997;157:2373-2376.

King JC, Keen CL. Zinc. In: Shils ME, Olson JA. Shike M,Ross AC, eds. Modem Nutrition in Health and Disease.Baltimore, MD: Williams and Wilkins; 1999:223-239.

Klug A, Rhodes D. "Zinc fingers": a novel protein motif fornucleic acid recognition. Trends Biochem Sci. 1987;5:464-469.

Levenson CWo Zinc supplementation: neuroprotective orneurotoxic?Nutr Rev. 2005;63(4):122-125.

Lonnerdal B. Dietary factors influencing zinc absorption. JNutr. 2000; 130(5S Suppl): 1378S-1383S.,Macknin ML. Zinc lozenges for the common cold. Cleveland

Clin J Med. 1999;66:27-31.

Macknin ML, Piedmonte M, Calendine C, et al. Zinc gluconatelozenges for treating the common cold in children. Arandomized controlled trial. JAMA. 1998;279: 1962-1967.

Mares-Perlman JA, Klein R, Klein BE, et al. Association ofzinc and antioxidant nutrients with age-related maculopathy.Arch Opthalmol. 1996;114:991-997.

Maret W, Sandstead HH. Zinc requirements and the risks andbenefits of zinc supplementation.J Trace Elem Med Bioi.2006;20( 1):3-18.

McMahon RJ, Cousins RJ. Mammalian zinc transporters. JNutr. 1998;128:667-670.

McMahon RJ, Cousins RJ. Regulation of the zinc transporter

ZnT-I by dietary zinc. Proc Natl Acad Sci USA. 1998;95:4841-4846.

Mocchegiani E; Zincage Consortium. Zinc, metallothioneins,longevity: effect of zinc supplementation on antioxidant

SUPPLEMENT MONOGRAPHS ZINC L-CARNOSINE /737

response: a Zincage study. Rejuvenation Res. 2008;11(2):419-423.

Mossad SB, Macknin ML, Medendorp SV, Mason PM. Zincgluconate lozenges for treating the common cold. Ann InternMed. 1996;125:81-88.

Natchu UC, Fataki MR, Fawzi WW. Zinc as an adjunct forchildhood pneumonia-interpreting early results. Nutr Rev.2008;66(7):398-405.

Newsome DA, Swartz M, Leone NC. Oral zinc in maculardegeneration. Arch Opthalmol. 1988;106:192-198.

Noseworthy MD, Bray TM. Zinc deficiency exacerbates loss ofblood-brain barrier integrity induced by hyperoxia measured bydynamic MRI. Proc Sac Exp Bioi Med. 2000;223: 175-182.

Nowak G, Szewczyk B, Pilc A. Zinc and depression. Anupdate. Pharmacal Rep. 2005;57(6):713-718.

O'Dell BL. Role of zinc in plasma membrane function. J Nutr.2000; 130:1432S-1436S.

Olsen RJ, Olsen P. Zinc as a treatment for age related maculardegeneration (review). J Trace Elem Exp Med. 1998;1I: 137-145.

Patro B, Golicki D, Szajewska H. Meta-analysis: zincsupplementation for acute gastroenteritis in children. AlimentPharmacal Ther. Epub: 2008 Jul I.

Prasad AS. Discovery of human zinc deficiency and studies inan experimental human model. Am J Clin Nutr. 1991;53:403-412.

Prasad AS. Zinc deficiency in women, infants and children. JAm Call Nutr. 1996;15:113-120.

Prasad AS. Zinc in human health: effect of zinc on immunecells. Mol Med. 2008;14(5-6):353-357.

Prasad AS. Zinc: mechanisms of host defense. J Nutr.2007; 137(5): 1345-1349.

Prasad AS. Zinc: the biology and therapeutics of an ion. AnnIntern Med. 1996;125:142-144.

Salgueiro MJ, Zubillaga M, Lysionek AK, et al. Zinc anessential micronutrient: a review. Nutr Rev. 2000;20:737-755.

Sandstead HH, Frederickson CJ, Penland JG. History of zinc asrelated to brain function. J Nutr. 2000; 130:496S-502S.

Sazawal S, Black RE, Bhan MK, et al. Zinc supplementation inyoung children with acute diarrhea in India. N Engl J Med.1995;333:839-844.

Schwartz JR, Marsh RG, Draelos ZD. Zinc and skin health:overview of physiology and pharmacology. Dermatol Surg.2005;31(7 Pt 2):837-47; discussion 847.

Solomons NW. Mild human zinc deficiency produces animbalance between cell-mediated and humoral immunity. NutrRev. 1998;56:27-28.

Stefanidou M, Maravelias C, Dona A, Spiliopoulou C. Zinc: amultipurpose trace element. Arch Toxicol. 2006;80(1): 1-9.

Sturniolo GC, Di Leo V, Barollo M, et al. The many functionsof zinc in inflammatory conditions of the gastrointestinal tract.J Trace Elem Exp Med. 2000; 13:33-39.

Temple VJ, Masta A. Zinc in human health. P N G Med J.2004;47(3-4): 146-158.

Tubek S. Zinc supplementation or regulation of its homeostasis:advantages and threats. Bioi Trace Elem Res. 2007; 119(I): 1-9.

Umeta M, West CE, Haidar J, et al. Zinc supplementation andstunted infants in Ethiopia: a randomized controlled trial.Lancet. 2000;355:2021-2026.

Zinc L-CarnosineDESCRIPTION

Zinc L-carnosine is a chelate of divalent zinc and thedipeptide L-carnosine. L-carnosine (see Carnosine) is com-prised of the nonprotein amino acid beta-alanine (see Beta-alanine) and the protein amino acid L-histidine.

Zinc L-carnosine was synthesized by the Japanese in the late1980s. It was first known as Z-I03 and later on aspolaprezinc. The idea for the synthesis of zinc L-carnosinecame from the knowledge that L-carnosine was reported toincrease granulation tissue and accelerate gastric healing inrats, and that zinc had been reported to have protective actionagainst various experimental gastric lesions and also hadbeen reported to possess antiulcer action in clinical studies.The thinking was that the combination of the beneficialeffects of zinc and L-carnosine under the chemical roof ofone molecule would make for a novel and potent antiulceragent. Japanese researchers found that the zinc L-carnosinecomplex did exhibit marked antiulcer activity against variousexperimental models of gastric ulcers and duodenal ulcers byacting directly on the gastric and intestinal mucosa. How-ever, even during the early days of zinc L-carnosineresearch, it was already demonstrated to have other activi-ties, such as inhibition of bone resorption in experimentalanimals. Recently, zinc L-carnosine entered the dietarysupplement marketplace in the United States.

Zinc L-carnosine is described chemically as 2-[(3-azanidyl-I-oxidopropy lidene )amino ] -3-(3H -imidazo 1-4-yI)propanoate.It is also known as polaprezinc, zinc carnosine, l3-alanyl-L-histidinato zinc, N-(3-aminopropionyl)-L-histidinato zinc,[N-I3-alanyl-L-histidinato(2- )-N,NN, Oa]zinc, and catena-(S)-(lm-[Na-(3-aminopropionyl)-L-histidinato (2-)-NJ,N2,O:Nr]-zinc]. Originally known as Z-103, zinc L-carnosine wasdemonstrated to be much more active against gastriculceration in rats than various other Zn(II) complexes. ZincD-carnosine was found to have little or no activity.Spectroscopic data indicated that the zinc ions coordinatewith L-carnosine to form a quadridentatel: I complex of

738/ZINC L-CARNOSINE PDR FOR NUTRITIONAL SUPPLEMENTS

polymeric nature in order to maintain low strain of thechelate rings. Small amounts of zinc L-camosine may befound in muscle and nervous tissue. (Carnosine in muscleand nervous tissue may form chelates with zinc, copper andiron.)

Zinc L-camosine's empirical formula is (C9HI2N403Zn)n, itsmolecular weight is 2SS.62, and its CAS Registry Number is107667-60-7. It is insoluble in water and common organicsolvents, but does dissolve in acid, including stomach acid.

Zinc L-carnosine is represented by the following chemicalstructure.

n

Zinc L-camosine


ACTIONS

Zinc L-carnosine has antiulcer, antigastritis and mucosalprotective activities. It may also have bone-protective andhepatoprotective activities.

MECHANISM OF ACTION

Antiulcer activity: In an early study of zinc L-camosine andpeptic ulcer disease, it was found that the agent preventedethanol-induced gastric mucosal damage in rats throughincreases in the activities of the gastric mucosal antioxidantenzymes superoxide dismutase (SOD) and glutathione per-oxidase (GSH-px). Zinc L-camosine also inhibited theincrease in thiobarbituric acid reactive substances (TBARS)in gastric mucosa injured by the ethanol. (TBARS is ameasure of oxidative stress.) The study authors concludedthat the protective mechanism of zinc L-carnosine againstgastric ulceration was due, at least in part, to the scavengingof oxygen-derived free radicals via increases in the synthesisof SOD and GSH-px in the gastric mucosa, induced by zincL-carnosine.

The antiulcer pharmacological effects of zinc L-carnosine onindomethacin-induced gastric lesions and acetic acid-inducedgastric ulcers, were found to be significantly greater thanthose of either of its components, L-carnosine and divalentzinc, or than a mixture of the two. In a study with rats, it wasdetermined that zinc L-camosine, which acts directly in

mucosal lesions, was retained in the stomach much longerand adhered to the ulcerous sites more strongly than diddivalent zinc or L-carnosine. The characteristics of thecompound were thought to arise from its much lowersolubility when compared to the high solubility of divalentzinc forms, such as zinc sulfate or L-carnosine.

In a study with primary monolayer cultures of rat gastricfundic mucosa, it was demonstrated that zinc L-carnosineprotected gastric cells from oxidative stress caused byhydrogen peroxide and ethanol in vitro, that ethanol-inducedcytotoxicity was linked with superoxide anion radicalproduction from cells, and that zinc L-carnosine-inducedprotection against ethanol seemed to be due, at least in part,to the scavenging of reactive oxygen species (ROS). Theauthors of the study concluded that zinc L-carnosine workedvia an antioxidant mechanism and directly protected gastricmucosal cells from noxious agents via its antioxidantproperties in vitro, independently of microcirculatory andneural or hormonal factors.

The antiulcer and mucocytoprotective effects of zinc L-carnosine may be explained, in part, by its antioxidantproperties, as well as its stimulative effect on mucussecretion and its membrane-stabilizing effect. However, thisdoes not completely explain the mechanism of action of itsantiulcer activity. In a study using gastric epithelial cells(MKN2S, a cell line derived from moderately differentiatedgastric carcinoma), it was reported that zinc L-carnosinesuppressed interleukin-S (IL-S) secretion induced by tumornecrosis factor-alpha (TNF-alpha) or interleukin-l beta (IL-lbeta) dose-dependently. IL-S messenger RNA expressionwas also inhibited by zinc L-carnosine. Proinflamrnatorycytokine nuclear factor-kappaB (NF-kappaB) activation inresponse to TNF-alpha, IL-l beta, phorbol ester, and hydro-gen peroxide, was downregulated by zinc L-carnosine.Further, Western blot analysis revealed inhibition of TNF-alpha-induced IkappaB-alpha phosphorylation in the pres-ence of zinc L-carnosine.

Thus, an anti-inflammatory action, specifically the down-regulation of proinflammatory cytokine-induced NF-kappaBactivation and IL-S expression in gastric epithelial cells, canbe added to the list of zinc L-camosine's antiulcer mecha-nisms of action.

To add yet another mechanistic possibility, zinc L-carnosinewas shown to inhibit indomethacin-induced apoptosis in therat gastric epithelial cell line RGM 1, a diploid and non-transformed epithelial cell line isolated from normal Wistarrat gastric mucosa. Pretreatment of the cells with zinc L-carnosine suppressed caspase-3 activation and subsequentapoptosis in the cells exposed to indomethacin, dose-depen-dently. Treatment of the cells with indomethacin did produce

SUPPLEMENT MONOGRAPHS ZINC L.CARNOSINE /739

ROS, but zinc L-camosine did not scavenge ROS in theindomethacin-treated cells, ruling out an antioxidant mecha-nism of action. Thus, in this case, zinc L-camosine inhibitedapoptosis via inhibition of caspase-3 activation, not byantioxidant activity.

Zinc L-carnosine was reported to help in the healing of acutegastric lesions in diabetic rats. In this case, enhancement ofmucosal insulin-like growth factor-l (IGF-I) messengerRNA expression was thought to contribute to the effect.

The effect of zinc L-camosine on cellular proliferation wasstudied in human umbilical vein endothelial cells (HUVEC),human foreskin fibroblasts and guinea pig gastric mucosalcells. Zinc L-carnosine stimulated cellular proliferation inthe HUVEC and the human foreskin fibroblasts, but did notstimulate proliferation in the guinea pig gastric mucosalcells. Stimulation of cellular proliferation was accompaniedby increased IGF-.I messenger RNA levels. The authors ofthe study concluded that their results suggested that thepromotion of wound healing by zinc L-carnosine was relatedto a proliferative effect on nonparenchymal cells, with zincand IGF-I being important for the action. Although divalentzinc in the form of zinc sulfate also demonstrated aproliferative effect, its action was much weaker than that ofzinc L-camosine.

The effects of the roles of inflammatory cytokines, neutro-phil accumulation and lipid peroxidation in the protectiveeffect of zinc L-carnosine against aspirin-induced gastricmucosal injury was examined in rats. Zinc L-carnosine dose-dependently inhibited the total gastric erosive area followingaspirin administration, inhibited increases in thiobarbituricacid-reactive substances (TBARS), an index of lipid peroxi-dation, and inhibited tissue-associated myeloperoxidase ac-tivity. TBARS and myeloperoxidase activity are bothmarkers of oxidative stress. In addition, zinc L-carnosinedose-dependently inhibited the aspirin-induced rise in theinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha). This study suggested that the protective effects ofzinc L-camosine on aspirin-induced gastric mucosal injurymay be attributed to its antioxidative and anti-inflammatoryactivities.

He/icobacter pylori is a common cause of chronic gastritisand peptic ulcer disease. In H. pylori-colonized gastricmucosa, activated neutrophils generate superoxide anionradicals and hydrogen peroxide. Myeloperoxidase in neutro-phils catalyzes the oxidation of chloride by hydrogenperoxide to produce hypochlorous acid. The hypochlorousacid reacts with ammonia generated by H. pylori to producemonochloramine, which is reactive, toxic and causes gastricmucosal cell injury via damage to DNA. Zinc L-carnosinehas been reported to inhibit H. pylori-'induced gastritis and

DNA damage in Mongolian gerbils through its scavengingaction against monochloramine.

The treatment of H. pylori is a course of triple therapy,usually with the two antibiotics-amoxicilIin and c1arithro-mycin-and a proton pump inhibitor. In a clinical study, aseven-day course of triple therapy with amoxicilIin, c1ari-thromycin and lansoprazole was found to be effective in H.pylori eradication, but the regimen was significantly im-proved by the addition of zinc L-camosine.

Zinc L-camosine has also been found to protect againstcolonic mucosal injury. A study investigated the effects ofzinc L-camosine on acetic acid-induced colonic mucosalinjury in rats in vivo. Zinc L-camosine inhibited visibledamage in the rat colonic mucosa and this was accompaniedby a significant increase in the expression of heat shockprotein 72 (HSP72) and suppression of nuclear factor-kappaB (NF-kappaB) activation in the colonic mucosa. Heatshock proteins protect cells against heat stress as well asother stressors. The authors of the study suggested that,based on the findings, zinc L-carnosine may be a noveltreatment for inflammatory bowel disease. The mechanismof action of this effect is not completely understood, butcontinued research in this area is needed and warranted.

Bone-protective activity: Zinc L-carnosine has been reportedto have possible antiosteoporosis and bone-sparing activities.However, the mechanism of action of these effects isunclear. In one study: prolonged administration of zinc L-carnosine to ovariectomized rats was found to prevent boneloss. In another study, using mouse marrow cultures, aninhibitory effect of zinc L-camosine on parathyroid hormone(PTH)-stimulated osteoclast-like cell formation was report-ed. It was speculated that the zinc L-camosine inhibition ofthe PTH-stimulated osteoclast-like cell formation was medi-ated via calcium-dependent activation of protein kinase C.

A small clinical pilot study of postmenopausal women withrheumatoid arthritis reported that zinc L-camosine improvedperiarticular osteoporosis, probably through an increase inbone formation.

Zinc L-camosine has been found to promote the differentia-tion of osteoblasts, to suppress the formation of osteoclastsand to prevent the progression of osteoporosis. Thesefindings, if they can be verified, could have powerfulapplications to promote new bone formation, includingperiodontal bone regeneration. High quality randomized,double-blind, placebo-controlled clinical trials are very muchneeded and warranted in order to learn if zinc L-carnosinehas any role to play in bone regeneration.

Hepatoprotective activity: Non-alcoholic steatohepatitis(NASH) is an increasingly common disorder, which may

740 {ZINC L-CARNOSINE PDR FOR NUTRITIONAL SUPPLEMENTS

have serious consequences. This has only recently beenrecognized. In some cases, it may lead to liver fibrosis,cirrhosis and even hepatocellular carcinoma. The pathogene-sis of NASH is unclear. Although a similar condition canoccur in people who abuse alcohol, NASH occurs in thosewho drink little or no alcohol.

The effects of zinc L-carnosine on the development ofNASH was investigated in a mouse model of the disease.Zinc L-carnosine was demonstrated to reduce lipid peroxida-tion, to suppress messenger RNA expression of proinflam-matory cytokines and to suppress the activation of hepaticstellate cells. (Stellate cell activation is the central event inhepatic fibrosis.) The results suggested that zinc L-camosineattenuated fibrosis in NASH by reducing lipid peroxidationand inflammation, and, during a later phase, promotingfibrinolysis by inhibiting tissue inhibitors of metalloprotein-ase expression.

In a small clinical trial of patients with earlyJiver cirrhosis, itwas reported that those patients who received zinc L-carnosine demonstrated reduction in the activity of tissueinhibitors of metalloproteinase-l as well as decreased levelsof type IV collagen, a marker of fibrosis.

Further research in this area is needed and warranted.

A few studies on the effects of zinc L-carnosine have alsobeen performed in patients with chronic hepatitis C infection.In one study, it was reported that zinc L-carnosine adminis-tration resulted in reduced hepatocyte injury as measured bythe increase in serum transaminase enzyme levels in patientswith hepatitis C who were on therapy with pegylatedinterferon alpha-2b and ribavirin. The mechanism of thiseffect was not clear. However, the authors of the studyspeculated that the effect of zinc L-carnosine had to do withits possible antioxidant activity.

In another study of patients with chronic ~epatitis Cinfection, it was'reported that those patients receiving zinc L-carnosine had reduced iron overload as determined by seriImferritin levels. Again, the mechanism of this eff~ct wasunclear.

PHARMACOKINETICS

There is very little on the pharmacokinetics (PK) of zinc L-carnosine in humans. Studies of the PK of zinc L-carnosinein rats show that, following ingestion, zinc L-carnosineslowly dissociates into its compo~ents, L-carnosine anddivalent zinc. Zinc L-carnosine, which acts directly inmucosal lesions, is retained in the stomach much longer thanother forms of divalent zinc and adheres to the mucosallesions and ulcerous sites much more than do divalent zincand L-carnosine themselves. The characteristics of thecompound may arise from its much lower solubility when

compared to the high solubility of divalent zinc, for example,in the form of zinc sulfate, and L-carnosine. One can think ofzinc L-carnosine in this regard as a slow-release form ofdivalent zinc and L-carnosine.

In the rat studies, zinc was found to be efficiently absorbedfrom the small intestine. However, it is unclear how' muchzinc L-carnosine, if any, is transported into the body. It isknown that following absorption, zinc is mainly bound toalbumin and transported from the intestine to the liver via theportal system. Zinc was found mainly excreted in the feces; asmall amount was found excreted in the urine. (See Zinc andL-carnosine for further information on the PK of zinc and ofL-carnosine.)


Zinc L-carnosine is a one-to-one complex of a syntheticderivative of carnosine and zinc. It is marketed as a zincsupplement with claimed benefits for gastric health. It mayhelp protect the liver against hepatitis C infection and otherstressors. It could have some radioprotective effects.

RESEARCH SUMMARY

Polaprezinc (zinc L-carnosine), an anti-ulcer drug which is achelate c<;>mpoundconsisting of zinc and L-carnosine, hasbeen used in a number of studies in which it demonstrates anability to protect against gastric mucosal injury. It inhibitedindomethacin-induced apoptosis in a rat gastric mucosal cellline in a dose-dependent manner, apparently by suppressingactivation of caspase-3, which plays a role in cell death bycleaving cellular protein substrates. An antioxidant mode ofaction was not observed in this study, and the zinc, ratherthan the L-carnosine, was thought to be responsible for thecaspase-3 inhibition. In another study, polaprezinc wasshown to inhibit Helicobacter pylori-associated gastritis ingerbil~. The authors believe the agent scavenged monochlo-ramine, which has been associated with H. pylori-associatedgastric mucosal injury. Rats administered zinc L-carnosinewere protected against acetic-acid induced colonic mucosalinjury in another study. The effect was attributed toinduction of heat shock protein 72 and suppression ofnuclear factor kappa B (NF-kB). The heat shock proteins arethought to have cytoprotectivefunctions in the presence ofvarious stressors. NF-kB is involved in inflammation. Theseauthors concluded that zinc L-carnosine may have significantpotential as a new therapeutic drug for inflammatory boweldisease.

More recently, a number of studies have suggested a possiblerole for zinc L-carnosine in the treatment of chronic hepatitisC infection. Human subjects with this disease were randomlyadministered 150 mg of polaprezinc daily for 48 weeks incombination with the drugs interferon and ribavirin and 300mg of vitamin E and 600 mg of vitamin C daily or, in the

SUPPLEMENT MONOGRAPHS ZINC L-CARNOSINE / 7411

case of the controls, the same regimen devoid of the zinc L-carnosine supplement. Increase in transaminase was signifi-cantly prevented in those receiving the zinc L-carnosine,compared with controls. The authors of this study concludedthat the zinc L-carnosine supplementation thus reducedhepatocyte injury during the treatment period and attributedthis favorable effect to an antioxidative action.

In another recent study of 14 patients with hepatitis C-relatedchronic liver disease, subjects were given polaprezinc 225mg/day for six months along with other medications. Thezinc L-carnosine supplement was credited in this study witha significant decrease in iron overload, thought to haveresulted from the supplement's anti-inflammatory activity inthe liver. The authors recommend zinc L-carnosine as acomplementary therapy for hepatitis C-related chronic liverdisease.

Also recently, another group of researchers has shown thatpolaprezinc attenuates liver fibrosis in a mouse model ofnon-alcoholic steatohepatitis. An inhibition of inflammationand lipid peroxidation was reported. Oral supplementationwith polaprezinc for 24 weeks resulted in benefit to patientswith early cirrhosis, again primarily due to hepatitis Cinfection, compared with controls.

The extent to which zinc L-carnosine supplementation canbe liver-protective in healthy individuals is unknown. Moreresearch is needed and warranted.

Noting that polaprezinc has exhibited various antiapoptoticeffects in the gut, researchers have recently examined theeffects of this substance on radiation-induced apoptosis in ratjejunal crypt cells. Pretreatment with the agent significantlyreduced the number of apoptotic cells. Whether this could beof benefit in ameliorating damage related, for example, toradiotherapy for pelvic malignancies demands further study.


CONTRAINDICA TIONS

Zinc L-carnosine dietary supplements are contraindicated in

those who are hypersensitive to any component of a zinc L-carnosine-containing supplement.

PRECAUTIONS

Those who wish to try a zinc L-carnosine supplement for ahealth condition should first discuss its use with his or herphysician.

Because of the lack of long-term safety studies on zinc L-carnosine dietary supplements, pregnant women and nursingmothers should avoid their use.

ADVERSE REACTIONS

No reports.

INTERACTIONS

DRUGS

H2 blockers (cimetidine, ranitidine,famotidine): The combi-nation of an H2 blocker and zinc L-carnosine may be moreeffective than when each agent is used alone.

Sucralfate: The combination of the cytoprotectant sucralfateand zinc L-carnosine may be more effective than when eachagent is used alone.


No known interactions:

FOOD

No known interactions.

HERBS

No known interactions.

OVERDOSAGE

There are no reports of overdosage from use of zinc L-carnosine supplements.


Zinc L-carnosine supplements are available in strengths of37.5 milligrams and 75 milligrams. Amounts used in mostgastric ulcer studies were 75 milligrams twice daily. Doseshigher than those recommended on the supplement labelshould not be exceeded.

LITERATURE

Fuji Y, Matsura T, Kai M, et al. Protection by polaprezinc, ananti-ulcer drug, against indomethacin-induced apoptosis in ratgastric mucosal cells. Jpn J Phannaco/. 2000;84(1 ):63-70.

Furuta S, Toyama S, Miwa M, et al. Residence time ofpolaprezinc (zinc L-carnosine complex) in the rat stomach andadhesiveness to ulcerous sites. Jpn J Pharmacol.1995;67(4):271-278.

Hamano H, Yoshinaga K, Eta R, et al. Effect of polaprezinc ontaste disorders in zinc-deficient rats. Riofactors. 2006;28(3-4):185-193.

Handa 0, Yoshida N, Tanaka Y, et al. Inhibitory effect ofpolaprezinc on the inflammatory response to Helicobacterpylori. Can J Gastroenterol. 2002; 16(11):785-789.

Hiraishi H, Sasai T, Oinuma T, et al. Polaprezinc protectsgastric mucosal cells from noxious agents through antioxidantproperties in vitro. Aliment Phannaco/ Ther. 1999;13(2):261-269.

Ishihara R, Iishi H, Sakai N, et al. Polaprezinc attenuatesHelicobacter pylori-associated gastritis in Mongolian gerbils.He/icobacter. 2002;7(6):384-389.

Ito M, Shii D, Segami T, et al. Preventive actions of N-(3-aminopropionyl)-L-histidinato zinc (Z-103) through increases inthe activities of oxygen-derived free radical scavenging enzymesin the gastric mucosa on ethanol-induced gastric mucosaldamage in rats. Jpn J Pharmacol. 1992;59(3):267-274.

742/ ZINC L-CARNOSINE PDR FOR NUTRITIONAL SUPPLEMENTS

Kishi S, Segawa Y, Yamaguchi M. Histomorphologicalconfirmation of the preventive effect of beta-alanyl-L-histidinatozinc on bone loss in ovariectomized ra~. Bioi Pharm Bull.1994; 17(6):862-865.

Korolkiewicz RP, Fujita A, Seto K, et aI. Polaprezinc exerts asalutary effect on impaired healing of acute gastric lesions indiabetic rats. Dig Dis Sci. 2000;45(6):1200-1209.

Maeno M, Ito-Kato E, Suzuki N, et aI. Effect of beta-alanyl-L-histidinato zinc on the differentiation pathway of humanperiodontal ligament cells. Life Sci. 2004;74(20):2493-2504.

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