free rad tissue antioxidant nutrients

8/13/2019 Free Rad Tissue Antioxidant Nutrients

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ree radical tissue damage protective role ofantioxidant nutrients 1

LAWRENCE J. M ACHLIN AND ADRIANNE BENDICHClinicalNutrition Hoffmann La Roche Inc. Nutley, New Jersey 07110, US A

ABSTRACTHighly reactive molecules called free radicals can causetissue damage by reacting with polyunsaturated fattyacids in cellu lar m embranes, nucleotides in DNA , andcritical sulfhydryl bonds in proteins. F ree radicals canoriginate endogenously from norm al metabolic reactionsor exogenously as components of tobacco smoke and airpollutants and indirectly through the metabolism of cer-tain solvents, drugs, and pestic ides as well as throughexposure to radiation. There is some evidence that freeradical damage contributes to the etio logy of manychronic health problem s such as em physem a, cardiovas-cular and inflammatory diseases, cataracts, and cancer.D efenses against free radical dam age include tocopherolvitam in E), ascorbic acid vitam in C), /3 .carotene, glu-tath ione, uric acid , bilirub in , an d several metal loenzymesinclud ing glu tathione peroxidase selen ium ), catalase iron), and superoxide dismutase copper, zinc, m an-ganese) and proteins such as ceruloplasm in copper).The extent of tissue damage is the result of the balancebetween the free radicals generated and the antioxidantp ro tectiv e d efen se system . S everal dieta ry m icro nu trien tscontribute greatly to the protective system . Based on thegrow ing interest in free radical b iology and the lack ofeffective therapies for many of the chronic diseases, theusefu lness of essential, safe nutrients in protectingagainst the adverse effects of oxidative injury warrantsfurther study . -MACHLIN, L. J. ; BENDICH, A . F ree rad-ical tissue damage: protective role of antioxidantnutr ients. FASEBJ 1: 441-445; 1987.Ke y Words: freeradicals antioxidants essential nutrientsm icronutrients tissue damage

THE FORM ATION OF HIGHLY REACTIVE, oxygen-contain ingmolecular species is a normal consequence of a varietyof essential b iochem ical reactions. If a reactive moleculecontains one or more unpaired electrons, the moleculeis termed a free radical. A s a result of the relative insta-bility of free radicals and their potential to damage cellsan d tissues, there are both enzymes an d small-molecular-weight molecules w ith antioxidant capabilities that canprotect against the adverse effects of free radical reac-

tions. There is, therefore , a critical balance between freeradical generation and antioxidant defenses. M any of th eprotective antioxidants are essential nutrients or have es-sential nutrients as part of their molecule. In the fieldof nutrition , the term essential is given to those nutrientslike the vitam ins) that must be consumed because thebody cannot synthesize these compounds.

The objective of th is review is to identify the sourcesof free radicals and the consequences of their reactionsw ith cellular components. In addition, the essentiald ietary nutrients that can protect against the damagingeffects of these reactive species are discussed. Particularemphasis is placed on the health implications of free rad-ical damage and the defensive role of dietary antioxidants.

SOURCES OF FREE RADICALSEndogenous sources of free radicals include those that aregenerated and act in tracellularly as well as those that areformed w ithin the cell and are released into the surround-ing area. In tracellular free radicals are generated fromthe autoxidation and consequent inactivation of smallmolecules such as reduced flavins and thiols, and fromthe activ ity of certain oxidases, cyclooxygenases, lipoxy-genases, dehydrogenases, and peroxidases. Oxidases andelectron transport system s are prim e, continuous sourcesof in tracellular, reactive oxygenated free radicals. E lectrontransfer from transition metals such as iron to oxygen-containing molecules can initiate free radical reactions.The sites of free radical generation encompass all cellularconstituents including m itochondria, lysosomes, perox-isomes, and nuclear, endoplasm ic reticular, and plasmamem branes as well as sites within the cytosol. M olecularspecies include, but by no means are lim ited to , hydroxyl,peroxy, hypochlorite, superoxide, and alkoxy radicals,and reactive molecules such as hydrogen peroxide andsinglet oxygen, which are not free radicals but are cer-tain ly reactive and capable of causing damage F ig. 1) 1).

Exogenous sources of free radicals include tobaccosmoke, certain pollutants and organic solvents, anesthet-

F rom the Sym posium presented by the A m erican Institu te o fN utrition at the 71st A nnu al M eeting of th e F ed era tio n o f A m eri-can Socie ties for E xperim enta l B io logy, W ash ington, D C, Apri l 2,1987. P articipants included B. A. F reem an, B . G oldste in, G . F .Co mb s , Jr T F Slater and L. J. Mach Im.


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Figure 1. C ellu lar sources of free radica ls . Adapted from ref 1.

ics, hyperoxic environm ents , an d pesticides. Some ofthese compounds as well as certain medications aremetabolized to free radical in termediate products thathave been shown to cause oxidative damage to the tar-get tissues. Exposure to radiation results in th e forma-tion of free radicals w ithin the exposed tissues 1-5).

CELLULAR TARGETS AND CONSEQUENCESOF FREE RADICAL DAM AGEPrim e targets for free radical reactions are the unsatu-rated bonds in membrane lip ids. Consequent peroxida-tion results in a loss in membrane flu idity and receptoralignment and potentially in cellular lysis. Free radicaldamage to sulfur-containing enzymes and other proteinsculm inates in inactivation, cross-linking, and denatura-tion. Nucleic acids can be attacked. Subsequent damageto the DNA can cause mutations that may be carcinogen-ic. Oxidative damage to carbohydrates can alter any ofthe cellu lar receptor functions including those associatedw ith hormonal and neurotransmitter responses 1-5).

Free radicals such as peroxy radicals, the superoxideanion, and the hydroxyl radical are responsible for manyof the damaging reactions. In addition , certain aldehydessuch as malondialdehyde and hydroxynonenal, arisingfrom the free radical degradation of polyunsaturated fattyacids, can cause cross-linkings in lip ids, proteins, andnucleic acids 1 , 5-7).

ESSENTIAL NUTRIENTS W ITHANTIOXIDANT FUNCTIONSOnly three essentia l nutrients can directly scavenge freeradicals. V itam in E a-tocopherol), the major lipid-soluble antioxidant present in all cellular membranes,protects against lipid peroxidation 8). V itam in E canact directly w ith a variety of oxy radicals, including theperoxy radical ROO .), Cd3., and HO . 9 , 10), as wellas w ith the superoxide radical Or) 11, 12). Tocopherol

can also react directly w ith singlet oxygen 13, 14). V ita-m in C ascorbic acid) is water soluble and, along w ithvitamin E, can quench free radicals as well as singlet oxy-gen. A scorbic acid has been shown to react directly w ithsuperoxide 15, 16), hydroxyl radicals 17), and singletoxygen 18). A scorbic acid can also regenerate thereduced, antioxidant form of vitam in E. In the presenceof transition metals, ascorbic acid can provoke the for-mation of free radicals. However, there is no evidencethat the autoxidative effect of ascorbic acid leads to thepromotion of lip id peroxidation 19).

It is quite clear that vitam in E does function as anantioxidant in vivo as evidenced by the increased con-centrations of aldehydes, peroxides, and lipofuscin in thetissues of vitam in E-deficient animals. S ignificantly in-creased levels of ethane and pentane in the exhaled airof vitam in E-deficien t rats as well as from vitam in C-deficient guinea pigs provide further evidence of in-creased lipid peroxidation when these nutrients are ab-sent from the diet 20, 21).

Recent work has shown that /3-carotene, a pigmentfound in all plants, is the most efficient quencher of sin-glet oxygen known in nature and can also function asan antioxidant 22). /3-Carotene is the m ajor caro tenoidprecursor of vitam in A . V itam in A, however, cannotquench singlet oxygen and has a very small capacity toscavenge free radicals 23, 24). /3-Carotene has been foundin cellu lar membranes, including those of lysosomes 25).These three nutrients are also present in relatively highconcentrations in the serum . The adrenal and pituitaryglands, the brain , white blood cells, p latelets, and thelens of the eye concentrate one or more of these nutrientsat levels up to 20-fold of that found in the serum 21).

There are, in addition, several nutritionally essentialm inerals incorporated into protective antioxidant en-zymes . Zinc, copper, and manganese are required forthe activ ity of the tw o types of superoxide dismutases.Selenium , an essentia l component of glutath ione perox-idase, is important in the decomposition of hydrogenperoxide and lipid peroxides. Catalase, a hemeprotein ,


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FR EER ADIC ALS AN D AN TIO XID ANT N UTRIEN TS 443

Figure Antioxidant protection w ith in the cell.

catalyzes the decomposition of hydrogen peroxide 26).G lutathione, in contrast to the other antioxidant defensesdiscussed, is a tripeptide composed of nonessential am inoacids Fig. 2).

It is important to note that the antioxidant enzymesare prim arily in tracellular and thus extracellu lar freeradicals, either endogenously produced or from the en-vironment, must be inactivated by the circulating an-tioxidants such as the direct acting vitam ins discussedabove as well as by ceruloplasm in, a copper-containingprotein Table 1).

The level of dietary intake of all the antioxidantm icronutrients directly affects the circulating level of thesenutrients and the activ ity of the antioxidant metalloen-zymes. Thus, low intakes of one or more of these an-tioxidant nutrients could reduce the bodys defensesagainst free radical damage and increase susceptib ilityto health problems associated with free radical damage.

ANTIOXIDANT INTERACTIONSIn addition to direct quenching of reactive, damagingfree radicals, vitam in C has been clearly shown to in-teract w ith the tocopheroxyl radical and to regeneratethe reduced tocopherol. The evidence for th is importantantioxidant function for ascorbic acid includes cell-freeexperim ents, investigations with liposomal membranes,and recently, in vivo evidence of higher concentrationso f v itam in E in tissues of guinea pigs fed high dietarylevels of vitam in C 19, 27).

V itam in E can protect the conjugated double bonds of/3-carotene from oxidation. The sparing action of toco-pherol on /3-carotene was first described in vivo in hu-mans by Urbach et al. 23).

V itam in E can protect against m any of the symptom s ofselenium defic iency and vice versa 26, 28). These sparingas well as synergistic actions are thought to result fromthe ability of both tocopherol and selenium -dependentglutath ione peroxidase to decrease the production of lip idperoxidation products F ig . 3).

Vitamins C and E/3-carotene

GlutathionePeroxidose

Peroxidase

A study of animals demonstrated that dietary sup-plementation w ith vitam in E or selenium alone wasineffective in preventing a chem ically induced mammarycancer. However, supplementation with both m icronu-trients prevented tumor development 29).

These m icronutrient interactions strongly indicate arequirement for optimal in take of all the antioxidantnutrients, because even a marginal deficiency in one canresult in a subsequent decrease in the bioactiv ity of otheressential m icronutrien ts even though recom mended levelsare c onsu med.TABLE 1. A ntio xid an t m ic ro nu tr ie nts

Nutrient Activity

V itam in C (ascorb ic acid ) Im portant w ate r-so lub le cy toso licc ha in -b re ak in g a ntio xid an t;reacts d irec tly w ith superox ide ,sing le t o xyg en; regeneratestoc ophero l from toc opheroxyradical

V ita min E (a -to co ph ero l) M ajor m em brane-bound, lip id-so lu b le ch a in - bre ak in ga ntio xid ant; re ac ts d irec tly w iths up ero xid e, s in gle t o xy ge n

3-Carotene M ost poten t sing le t oxygenquencher, antiox idant p rope rtiesparticularly at low oxygenp ressure, lip id so lub le

Zinc C onstituent of cytosolics up ero xid e d is mu ta se

Selen ium C onstituent of g lu ta th ioneperoxidase

C opper C onstituent of c ytosolicsuperox ide dism utase andceru lop lasmin

Iron C onstituent of cata laseManganese C onstituent of m itocho ndria l

s up ero xid e d is mu ta se


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P U FA p ero xid es I Vitam in E V itam in C . an d ra dic alsAct ivated _(Oxygen PUFA alcoholsX Vitamin Vitamin c)

NN Vitamin E

N (o-tocopheroI)10NA ctivated______ N ./3-caroten d iet

//3-caro ene\ V itam in E n Isperoxidotionenergy

44 4 M A CH LIN A ND B EN DIC H

Figure 3. M icronutrient in teractions in the antiox idant defense system .

HEALTH IMPLICATIONS OF FREERADICAL DAMAGEThe range of antioxidant defenses available w itih in thecell and extracellu larly should be adequate to protectagainst oxidative damage. H owever, the balance can belost because of overproduction of free radicals, by ex -posure to sources that overwhelm the antioxidantdefenses, or by inadequate intake of nutrients that con-tribute to the defense system .

The lungs are continuously exposed to oxygen, air pol-lutants, and tobacco smoke, even lungs of nonsmokers.Exposure to hyperoxic conditions after premature birtho r d eg en er at iv e lung disease increases th e potential foroxidative damage. Continuous exposure to free radical-containing environmental pollutants has been associatedwith lung damage, emphysema, and cancer 30, 31).

The circulating levels of selenium , vitam in C , and /3-carotene are lower in smokers than in nonsmokers 32,33). Lower consumption of foods containing vitam insC , E , and A, /3-carotene, and selenium has been as-sociated in numerous epidemiological studies w ith in-creased risk for lung and other cancers, and a recentstudy correlated lower circu lating levels o f v ita min E and/3-carotene w ith significantly greater risk of lung cancer34).

In addition to lung cancer, lower risk of colon cancerhas been associated w ith higher dietary intakes of vita-m in E and C, /3-carotene, and selenium 35, 36). Lowercirculating levels of /3-carotene, v itam in C, and vitaminE have been found in precancerous dysplasias of the cer-vix and intestine . In most of these studies, a completean tiox idan t nutritional analysis was not perform ed;however , based on the interactions of these nutrients, iti s r ec om m e nd ed that future investigators evaluate theirdata for sim ilar correlations.

Vitamin C(ascorbate)

Cardiovascular diseases including atherosclerosis andth e card iac tissue in jury after m yocard ial infarction havebeen shown to result in part from free radicals gener-ated at the site of damage. Both vitam in E and superox-ide dismutase have been used therapeutically w ith suc-cess in lowering the oxidative insult after ischem ia 6).A large, multinational epidem iological study suggests thathigher dietary intake and blood levels of the antioxidantvitam ins and selenium are associated with reduced riskof mortality from cardiovascular disease 36, 37).

In addition to the diseases mentioned above, the for-m ation of cataracts, the photoderm atoses, inflam matorydiseases including arthritis, and the aging process itselfhave all been associated w ith free radical damage. Sup-plementation of laboratory anim al d iets w ith a nti ox id an tnutr ients ha s in m any cases prevented th e d ev elo pm e ntof these degenerative conditions 6, 19, 24, 31, 38-40).

REFERENCES1. FREEMAN, B. A .; Ca.uo , J. D . B iology of disease: free

radicals an d tissu e inju ry . L ab . I nv es t. 47: 412-426; 1982.2. SLATER, T. F. F ree radical m echanism s in tissue injury. Lon-don: P ion; 1972.3. TAYLOR, A. E.; MATALON , S .; WAR D , P . A ., EDS . Physiologyfo xyg en r ad ica ls . Bethesda: A m. Physiol. Soc; 1986.4. SIES, H . Oxidative stress: introductory remarks. S ies, H .,ed . O xid ativ e s tr es s. New York: Academic; 1985: 1-8 .5. HALLIWELL , B.; GUTTERIDGE, J. M. C . Freeradicals inbiolog y a nd m ed ic in e.Oxford , England: C larendon; 1985.6. FLOHE, L.; BECKMANN , R .; GIERTZ , H .; LOSCHEN, G .Oxygen-centered free radicals as mediators of inflam-mation. S ies, H ., ed. O xid ativ e s tr es s. New York: Aca-demic; 1985: 405-437.7. SLATER, T. F . Free radical-m ediated tissue dam age. Nutri-tion 19 87. Bethesda: Am . Inst. Nutr. In press.8. MACHLIN, L. J. Vitam in E: a comprehensive treatise. NewYork: Dekker; 1980.


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9. M CCAY , P. B . V itam in E: interactions w ith free radi-cals and ascorbate. Annu. Rev. Nutr. 5: 323-340; 1985.

10 . BURTO N, G. W .; FOSTER, D. 0.; PERLY, B .; SLATER,T. F .; SMITH, I. C . P. ; ING0LD, K. U . Biological an-tioxidants. P hi lo s.T ra ns . R . S oc . L o nd . B B io l. Sc i.311:565-578; 1985.

11 . FUKUZAWA, K.; GEBICKI , J. M . Oxidation of alphatocopherol in m icelles and liposomes by the hydroxyl,perhydroxyl, and superoxide free radicals. Arch. Biochein.Biophys. 226: 242-251; 1983.12 . OZAWA , T.; HANAKI , A.; MATsuo , M. Reactions of su-peroxide ion w ith tocopherol and m odel com pounds:correlation between the physio logical activities oftocopherols and the concentration of chromanoxyl-radicals. Biochem. Int. 6: 685-692; 1983.

13 . FAHRENHOLTZ , S . R .; DOLEIDEN, F. H .; TRozzoLo,A . M .; LAMOLA, A . A . On the quenching of singlet oxy-gen by alpha-tocopherol. P ho loc hem . P ho tob iol. 20 :505-509; 1974.14 . LITTARRU, G. P.; LIPPA, S. ;DE SOLE , P .; ORADEI , A. ;D AL LA TO RR E, F. ; M ACRI, M . Quenching of singlet oxy-gen by D-alpha-tocopherol in hum an granulocytes. Bi-ochem. Biophys.Res. Commun. 119: 1056-1061; 1984.

15 . HEMILA , H .; ROBERTS , P .; W IKSTROM , M . A ctivatedpolymorphonuclear leucocytes consume vitam in C .FEBSLet t . 178: 25-30; 1985.

16 . NISHIKIM , M . Oxidation of ascorbic acid w ith superox-ide anion generated by the xanthine-xanthine oxidasesystem. Biochem. Biophys. Res. Commun. 63: 463-468;1975.

17 . BIEL5KI, B . H . Chem istry of ascorbic acid radicals. A s-corb ic acid: chem istry , m etabolism , and uses. Ado.Chem. Ser. 2 00 : 8 1- 10 0; 1 98 2.18. BODANNE5 , R . S .; CHAN, P. C . Ascorbic acid as ascavenger of singlet oxygen. FEBS Lett. 10 5: 1 95-1 96 ;1979.

19 . BEND ICH , A.; M AC HL IN , L .J.; SCANDURRA, 0. ; BURTON ,G . W .; WAYNER , D. M . The antioxidant ro le of v ita-m in C . Ado. Free Radical B iol. M ed. 2: 419-444; 1986.

20 . KUNERT , K. J. ; TAPPEL , A . L . The effects of v itam in Con in vivo lip id peroxidation in guinea pigs as meas-ured by pentane and ethane production . Lipids 18 :271-274; 1983.21. M ACHLIN , L. J. Protective role of vitam ins against freeradical tissue dam age. N utrition 1987. Bethesda: Am .Inst. Nutr. In press.

22 . BURTON, G . W .; INGOLD, K . V . Beta carotene: an un-sual type of lipid antioxidant. ience 224:569-573; 1984.

23. URBACH, C.; HICKMAN, K.; HARRIS , P. L . E ffect of in-d ividual vitam ins A , C , E and caro tene adm inisteredat h igh levels and their concentration in the blood. Exp.M ed. Surg. 1 0: 7 -2 0; 1 95 1.

24 . MATHEWS-ROTH, M. M . Beta carotene therapy forerythropoietic protoporphyria and other photosensitiv-it y d is ea se s. Biochemie 68: 875-884; 1986.25 . MAYNE , S . T. ; PARKER , R . S . S ubcellular distribution

o f d ie ta ry b et a c ar ot en e i n c hi ck l iv er .Lipids 21 :164-169; 1986.

26 . COMBS , J. F. ,J it.Prot ec tivero le sof minerals against freeradical tissue dam age. Nutrition 1987. Bethesda: Am .Inst. N utr. In press.

27 . BENDICH, A.; D IAP0LITO , P.; GABRIEL, E .; M ACHUN,L . J. In teraction of dietary vitam in C and vitam in Ein guinea pig im mune responses to m itogens. J. Nutr .114: 1588-1593; 1984.

28 . GANTHER, H . E.; HAFEMAN , D. G .; LAWRENCE , R . W .;SERFASS , R. E.; HOCKSTRA, W . G . Selenium andglu tath ione peroxidase in health and disease. A review .Prascil. Prasad , A . S .; O berleas, D ., eds. T ra ce e lem en tsin h um an he alth an d iseose Vol. 2. N ew York: Academ ic;1976: 165-235.

29. HORVATH , P . M .; It, C . Synergistic effect of vitam in Ean d selen ium on the chemo prevention of m am mary car-cinogenesis in rats. Cancer Res. 43: 5335-5341; 1983.

30. FRIDOvICI-I , I. ; FREEMAN, B. Antioxidant defenses in thelung. A nn u. R ev . P hy si ol .48: 693-792; 1986.

31 . TATE , R . M .; REPINE , J. E . Phagocytes, oxygen radi-cals and lung in jury . P ryor, W . A ., ed . F re e r ad ic als inbiology, Vol. 6. N ew York: Academ ic; 1984: 199-212.32 . C HOW , C. K .; THACKER, R. R.; CHANGCHIT , C .;BRIDGES , R . B.; R EHM, S . R .; HUMBLE , J. ; TURBEK,J. Low levels of vitam in C and carotenes in plasma ofcigarette sm ok ers.j Am. CoIl. Nutr. 5: 305-3 12; 1986.33 . SALONEN, J. T. ; SALONEN, R. ; LAPPETELAINEN, R .;MAENPAA , P .; A LFT HA N, G .; PUSKA, P . R isk of cancerin relation to serum concentrations of selen ium an d vita-m ins A and E: matched case-control analysis o f p ro sp e c-tive data. Br. M ed. J. 290: 417-420; 1985.

34 . MENKES , M. S.; C0MSTOCK, G . W .; VUILLEUMIER, J . P .;HELSING, K. J. ; RIDER, A. A.; BROOKMEYER , R. Se-rum beta carotene, v itam ins A and E, selen ium and therisk of lung cancer. N. Engl. J. Med. 3 15 : 1 250 -12 54;1986.

35 . STXHELIN, H. B .; R3SEL, F .; BUESS , E. ; BRUBACHER , G .Cancer, v itam ins, and plasma lip ids: prospective Baselstudy. J. Nail. C ancer Inst. 73: 1463-1468; 1984.

36. GEY , L . F .; BRUBACHER , G . B .; STAHELIN , H . B . P lasm alevels of antioxidant v itam ins in relation to ischaem icheart d isease and cancer. Am . J. Clin. Nutr. 45:1368-1377; 1987.

37. GEY , F . On the antioxidation hypothesis w ith regard toatherosclerosis. B ibI. N utr. Dicta 37: 53-91; 1986.

38. COHEN , G . Oxidative stress in the nervous system . Sies,H., ed . Oxidative stress.New York: Academ ic; 1985:383-403.

39 . HIRSCHELMANN, R .; BEKEM EIER , H . E ffects of catalase,peroxidase, superoxide dismutase and 10 scavengers ofoxygen radicals on carrageenin edem a and adjuvant ar-thritis of rats. E xp er ie ntia B as el) 37: 1313-1314; 1981.

40. CUTLER, R . G . Aging and oxygen radicals. Taylor, A . E .;M atalon, S.; Ward, P. A ., eds. P hy siolo gy o f o xy gen radicals.Bethesda: Am . Physiol. Soc.; 1986: 251-285.

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