CURCUMIN13FET1003: Moksha Chib13FET1004: Ameya Pathak

The Indian Solid Gold

• Curcumin is extracted from turmeric which is derived from rhizome of the plant Curcuma longa

• Curcuminoids give turmeric its characteristic yellow color• Curcumin ( ): is an orange-yellow crystalline powder which is

the most active component of turmeric, which makes up 2-5% of the spice

• Curcumin has been shown to be a diferuloylmethane• It is hydrophobic in nature and is soluble in dimethylsulfoxide, acetone,

ethanol and oils• It is also referred to as Indian saffron, yellow ginger, yellow root,

kacha haldi, ukon or natural yellow 3

12 20 6C H O

Chemical Composition• Insoluble in water & ether• Soluble in ethanol, dimethylsulfoxide & acetone• Has a melting point of 183°C• Molecular formula : • Molecular weight: 368.37g/mol• Turmeric contains curcumin along with other

constituents known as “curcuminoids”

Curcumin (Curcumin I) Demethoxycurcumin (Curcumin II) Bisdemethoxycurcumin (Curcumin III) Cyclocurcumin

• Commercial curcumin contains curcumin I (~77%), curcumin II (~17%) & curcumin III (~3%)

• Curcumin has a brilliant yellow hue at pH 2.5 & takes a red hue at pH>7

12 20 6C H O

Food sourcesMajor source of curcumin obtained from Curcuma longa & is used as a spice in Indian, South Asian, Middle Eastern cuisines. Curry powders have variable and relatively low amount of curcumin.

Curcuma aromatica, Curcuma phaeocaulis (3%), Curcuma zedoaria (0.1%), Curcuma mangga, Curcuma xanthorrhiza (1-2%), Costus speciosus, Zingiber cassumunar, Etlingera elatior

Curcumin extracts used as dietary supplements are standardized to contain 95% curcuminoids (not strictly regulated by US FDA). Curcumin extracts are also used as food-coloring agents.

TURMERIC

OTHER PLANTS

EXTRACTS

MEDICINAL PROPERTIES OF CURCUMIN

METABOLISM OF CURCUMIN• Once absorbed, curcumin is subjected to

sulfation and glucuronidation at various tissue sites (majorly, liver)

Major biliary metabolites: Glucuronides of tetrahydrocurcumin (THC) & hexahydrocurcumin (HHC)

Minor metabolites: Dihydroferulic acid together with traces of ferulic acid

• Orally administered curcumin is absorbed from the alimentary tract and present in the general blood circulation after largely being metabolized to the form of glucuronide/sulfate conjugates

• There is no clear understanding on whether curcumin metabolites are as active as curcumin

• Some studies found that THC showed better anti-diabetic & antioxidant activity in type 2 diabetes & much lower anti-inflammatory & anti-proliferative activity

BIOAVAILABILITY OF CURCUMIN

SERUM CONCENTRATIONS

• Curcumin is poorly absorbed from the gut

ORAL: Admin. of 1.0g/kg showed low plasma levels (0.13µg/mL) after 15min, max. plasma level (0.22µg/mL) after 1h, which then declined below detection limit by 6hI.V/I.P: Plasma levels peaked (2.25µg/mL) within 15min of admin. & declined rapidly within 1h

• Serum levels in rats & humans are not directly comparable

TISSUE DISTRIBUTION• Oral admin. of 400mg showed that

only traces of unchanged drug was found in the liver & kidney and 90% was found in the stomach after 30min which was reduced to 1% after 1h

• The percentage of curcumin absorbed (60-66%) remained constant regardless of the dose

• I.P route showed max. amount of curcumin in the intestine after 1h; spleen, liver & kidney showed moderate amounts whereas only a trace amount was found in brain tissue

HALF LIFE• It was reported that when

1g/kg curcumin was given orally to rats, 75% of it was excreted in feces & negligible amounts were found in urine

• The absorption & elimination half-lives of orally administered curcumin in rats was found to be 0.31 & 1.7h respectively

• Half-lives in humans were not found since the serum levels were below the detection limits

STABILITY OF CURCUMIN

• Curcumin is unstable at neutral and basic pH & is degraded to ferulic acid & feruloyl methane

• More than 90% of the curcumin decomposes rapidly in buffer systems at neutral-basic pH & this degradation occurs due to oxidative mechanism

• Curcumin is also unstable in phosphate buffer at pH 7.4

• Curcumin is expected to be stable in stomach and small intestines since the pH is between 1 to 6 & the degradation is really slow in these conditions

• Curcumin exists in polar solvent as keto-enol tautomer & as diketo tautomer in non-polar solvents

The poor absorption from the intestine, coupled with high degree of metabolism of curcumin in the liver and it’s rapid elimination in the bile, makes it unlikely that high concentrations of the substance would be found in the body long periods of time after ingestion

8Reasons of Why You Should Spice It Up!

ANTIOXIDANT ACTIVITY• Curcumin is known to protect biomembranes against

peroxidative cell membrane damage (free-radical-mediated chain reaction)

• The inhibition of peroxidation by curcumin is mainly attributed to the scavenging of the reactive free radicals involved in the peroxidation.

• Theoretical calculations have shown that the enol form of curcumin is more stable than the keto form and the BDE of the phenolic O-H bond is significantly lower than that of the central O-H,suggesting that the hydrogen atom extraction takes place at the phenolic group

• Litwinienko and Ingold recently proposed the sequential proton loss electron transfer theory (SPLET) in ionizing solvents and H-Atom Transfer (HAT) mechanism in non-ionizing solvents

ANTI-INFLAMMATORY ACTIVITY• The anti-inflammatory effect of curcumin is most likely mediated through

its ability to inhibit cyclooxygenase-2 (COX-2), lipoxygenase (LOX), and inducible nitric oxide synthase (iNOS).

Effect of Curcumin on Cyclooxygenases and Lipoxygenases• Curcumin suppresses prostaglandin (PG) synthesis. PG is involved in

human cancer development (carcinogen metabolism, tumour cell proliferation). COX is a key enzyme responsible for conversion of arachidonic acid (AA) to PGs. AA metabolites derived from LOX pathways play an important role in growth related signal transduction (contributing to cancer development). Curcumin is shown to inhibit both COX and LOX activities

Effect of Curcumin on Inducible Nitric Oxide Synthase• iNOS catalyzes the oxidative deamination of L-arginine to produce NO, a

potent pro-inflammatory mediator. NO has multifaceted roles in mutagenesis and carcinogenesis.NO reacts rapidly with superoxide anion to produce peroxynitrite (ONOO-) which can cause harmful DNA modifications and actiavtes the tumout suppressor gene p53 or PARP which is associated with apoptic cell death. iNOS also regulates COX-2 Curcumin has been shown to inhibit iNOS gene expression.

GLUTATHIONE SYNTHESIS

• Glutathione is an important intracellular antioxidant that plays a critical role in cellular adaptation to stress.

• Stress-related increases in cellular glutathione levels result from increased expression of glutamate cysteine ligase (GCL), the rate-limiting enzyme in glutathione synthesis.

• Studies in cell culture suggest that curcumin can increase cellular glutathione levels by enhancing the transcription of genes that encode GCL

CANCER

• Because inflammation is closely linked to tumor promotion, curcumin with its potent anti-inflammatory property is anticipated to exert chemopreventive effects on carcinogenesis

• Curcumin has been shown to protect against skin, oral, intestinal, and colon carcinogenesis and also to suppress angiogenesis and metastasis in a variety animal tumor models

• It also inhibits the proliferation of cancer cells by arresting them in the various phases of the cell cycle and by inducing apoptosis

• Curcumin has a capability to inhibit carcinogen bioactivation via suppression of specific cytochrome P450 isozymes, as well as to induce the activity or expression of phase II carcinogen detoxifying enzymes.

CANCER

Effects on biotransformation enzymes involved in carcinogen metabolism • Biotransformation enzymes play important roles in the metabolism and elimination of a variety of biologically active compounds, including drugs and carcinogens. • In general, phase I enzymes, including those of the cytochrome P450 (CYP) family, preparing them for reactions catalysed by phase II biotransformation enzymes. Dietary curcumin increases the activity of phase II enzymes

Induction of cell cycle arrest and apoptosis• Defective cell-cycle regulation may result in the propagation of mutations that contribute to the development of cancer. Curcumin has been found to induce cell-cycle arrest and apoptosis in a variety of cancer cell lines grown in culture (1, 31-35). The mechanisms by which curcumin induces apoptosis are varied but may include inhibitory effects on several cell-signalling pathways

Inhibition of tumor invasion and angiogenesis• Cancerous cells invade normal tissue with the aide of enzymes

called matrix metalloproteinases. Curcumin has been found to inhibit the activity of several matrix metalloproteinases in cell culture studies. To fuel their rapid growth, invasive tumors must also develop new blood vessels by a process known as angiogenesis. Curcumin has been found to inhibit angiogenesis in cultured vascular endothelial cells and in an animal model

CYSTIC FIBROSIS

• Cystic fibrosis is a hereditary disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.

• CFTR is a transmembrane protein that acts as a chloride channel and plays a critical role in ion and fluid transport.

• In the lungs, CFTR mutations ultimately result in increased mucus concentration and decreased mucus clearance, which leads to progressive lung disease.

• In 2004, a study in mice with the DeltaF508 mutation found that oral curcumin administration corrected abnormal ion transport and improved the survival of these mice.

• However, it is unclear whether curcumin supplementation will be of benefit to humans with cystic fibrosis.

ALZHEIMER’S DISEASE• In Alzheimer’s disease, a peptide called amyloid β forms

aggregates (oligomers), which accumulate in the brain and form deposits known as amyloid plaques.

• Inflammation and oxidative damage are also associated with the progession of Alzheimer’s disease.

• Curcumin has been found to inhibit amyloid β oligomer formation in vitro.

• When injected peripherally, curcumin was found to cross the blood brain barrier in an animal model of Alzheimer’s disease.

• In animal models of Alzheimer's disease, dietary curcumin has decreased biomarkers of inflammation and oxidative damage, amyloid plaque burden in the brain, and amyloid β-induced memory deficits

• It is not known whether curcumin taken orally can cross the blood brain barrier or inhibit the progression of Alzheimer’s disease in humans

ANTI-HIV ACTIVITY

• Curcumin inhibits the LTR (Long Terminal Repeat ), a sequence of viral HIV DNA which activates the viral genome.

• Proposed mechanisms are:1. Prevent the binding at its DNA binding site.2. It may inhibit protein kinase C (HIV

protease enzyme)

SKIN DISEASES• Curcumin protects skin by quenching free

radicals and reducing inflammation through nuclear factor-kB inhibition.

• Curcumin treatment also reduced wound healing time, improved collagen deposition and increased fibroblast and vascular density in wounds thereby enhancing both normal and impaired wound-healing.

• Curcumin has also been shown to have beneficial effect as a proangiogenic agent in wound-healing by inducing transforming growth factor-kB, which induces both angiogenesis and accumulation of extracellular matrix, which continues through the remodeling phase of wound repair.

EXTRACTION OF CURCUMIN FROM TURMERIC Various approaches have been followed on the extraction or isolation of curcumin from turmeric. Solvent extraction (the most conventional method)Supercritical CO2 extraction Ultra-sonic irradiation (40% curcumin yield)Microwave extraction (68.75% curcumin yield)Water soaked irradiation (71.42% curcumin yield)

SOLVENT EXTRACTION OF CURCUMIN The extraction process is carried out in two steps- selective removal of the turmeric oil and extraction of pigments1. Rhizome is de-oiled by hexane, which has a poor selectivity for coloring matter2. The residue is then freed from the solvent & exhaustively extracted with another solvent

like methanol to recover curcumin. After removing the solvent, the concentrated extract is dissolved in alkali, filtered & acidified with acid to precipitate the pigment

Powdering Solvent extraction

Partial concentratio

nCrystallization

Removal of crystals by

centrifugation

Purification of crystals by

washing

Solvent removal by

steam

Drying

Powderin

g

TURMERIC

CURCUMIN

DRUG-DRUG INTERACTIONS

TYPE OF DRUG MECHANISM EXAMPLESAnticoagulant/ Antiplatelet

Inhibit platelet aggregation suggesting a potential for curcumin supplementation to increase the risk of bleeding in people taking these drugs

Aspirin, Clopidogrel (Plavix), Dalteparin (Fragmin), Enoxaparin (Lovenox), Heparin, Ticlopidine (Ticid) & Warfarin (Coumadin)

Chemotherapeutic agents in Breast cancer

Inhibits apoptosis induced by these agents. Dietary curcumin was found to inhibit cyclophosphamide-induced tumor regression.

Camptothecin, Mechlorethamine, Doxorubicin

CURCUMIN + PIPERINE = A PERFECT MATCH

Piperine has been found to increase the bioavailability & absorption of curcumin in both rats and humans with no adverse effects• Upon oral administration of curcumin with piperine, curcumin could be

found in blood even up to 8 days• The amounts of curcumin present in blood, liver tissue, kidney & brain

tissue were found to be higher than what is found when curcumin is administered alone

• Excretion of intact curcumin in the urine was relatively higher compared to what was seen when curcumin was administered alone & accounted for 1.43% of the dose administered

• Serum concentrations of curcumin were found to be higher • Bioavailability increased by 154% whereas elimination half life &

clearance decreased significantly• The extent of absorption of curcumin when taken with piperine

(humans) is 78% compared to 63.5% absorption observed when administered alone

SAFETY AND TOXICOLOGY• Has GRAS status in the USA.• Serious adverse effects have not been reported in humans taking high doses of curcumin. • A dose escalation trial in 24 healthy adults found that single oral dosages up to 12 g were safe, and adverse effects were not dose-related.• 20-40 mg supplementation reported to increase gallbladder contractions in healthy people.• Mild nausea and diarrhoea experienced by two participants in a UK based clinical trial where curcumin supplementation of 0.45-3.6 g/ day was given for 4 months to cancer patients.• The maximal tolerated dose, a traditional end point for anticancer chemotherapy, of curcumin has not been reached in these studies.

SAFETY AND TOXICOLOGY• Pregnancy and lactationWhile studies in pregnant rats, mice, guinea pigs, and monkeys suggested that the use of turmeric or curcumin is safe for those animals in pregnancy, there have been no studies involving pregnant women subjects reported to date.• Based on studies on possible interactions of turmeric with other herbs or medicines,

it can be advised that turmeric (or curcumin supplements) should not be used in the following circumstances without prior consultation with a qualified medical practitioner:

1. People who are on blood thinning medications, e.g., warfarin, aspirin, etc. 2. People who are on nonsteroidal anti-inflammatory drugs, e.g., indomethacin, ibuprofen, etc. 3. People who are on the hypotensive drug, reserpine.

MARKETED PRODUCTS OF CURCUMIN

Zenith Nutrition Curcumin Plus- 500mg

CURCUMIN CAPSULES

60 vegetarian capsules per pack, powerful antioxidant, natural anti-inflammatory compound Rs 639

Contains piperine (5mg/serving), 500mg curcumin/serving, 60 vegetarian capsule servings per bottle,

Dosage: 1 capsule twice a day, Rs. 873

Natural combination of joint-supporting boswellia & curcumin, no fillers or artificial ingredients, 90 capsules, Rs.1599

Boswellia Turmeric 500mg Extract

Himalaya Haridra

400mg curcumin extract per capsule, 60 vegetarian capsules per pack, Dosage: 1 capsule, twice a day after meals, Rs. 100

THANK YOU!