INDIA has a rich history of using plants for medicinal purposes. Turmeric (Curcuma longa L.) is a medicinal plant extensively used in Ayurveda, Unani and Siddha medicine as home remedy for various diseases. C. longa L., botanically related to ginger (Zingiberaceae family), is a perennial plant having a short stem with large oblong leaves and bears ovate, pyriform or oblong rhizomes, which are often branched and brownish-yellow in colour. Turmeric is used as a food additive (spice), preservative and colouring agent in Asian countries, including China and South East Asia. It is also considered as auspicious and is a part of religious rituals. In old Hindu medicine, it is extensively used for the treatment of sprains and swelling caused by injury. In recent times, traditional Indian medicine uses turmeric powder for the treatment of biliary disorders, anorexia, coryza, cough, diabetic wounds, hepatic disorders, rheumatism and sinusitis. In China, C. longa is used for diseases associated with abdominal pains. The colouring principle of turmeric is the main component of this plant and is responsible for the antiinflammatory property. Turmeric was described as C. longa by Linnaeus and its taxonomic position is as follows:
Class : Liliopsida
Subclass : Commelinids
Order : Zingiberales
Family : Zingiberaceae
Genus : Curcuma
Species : Curcuma longa
The wild turmeric is called C. aromatica and the domestic species is called C. longa.
Chemical composition of turmeric
Turmeric contains protein (6.3%), fat (5.1%), minerals (3.5%), carbohydrates (69.4%) and moisture (13.1%). The essential oil (5.8%) obtained by steam distillation of rhizomes has a-phellandrene (1%), sabinene (0.6%), cineol (1%), borneol (0.5%), zingiberene (25%) and sesquiterpines (53%)5. Curcumin (diferuloylmethane) (3–4%) is responsible for the yellow colour, and comprises curcumin I (94%), curcumin II (6%) and curcumin III (0.3%)6. Demethoxy and bisdemethoxy derivatives of curcumin have also been isolated. Curcumin was first isolated8 in 1815 and its chemical structure was determined by Roughley
and Whiting in 1973. It has a melting point at 176–177°C; forms a reddish-brown salt with alkali and is soluble in ethanol, alkali, ketone, acetic acid and chloroform.
Biological activity of turmeric and its compounds
Turmeric powder, curcumin and its derivatives and many other extracts from the rhizomes were found to be bioactive. Turmeric powder has healing effect on both aseptic and septic wounds in rats and rabbits. It also shows adjuvant chemoprotection in experimental forestomach and oral cancer models of Swiss mice and Syrian golden hamsters. Curcumin also increases mucin secretion in rabbits. Curcumin, the ethanol extract of the rhizomes, sodium curcuminate, [feruloyl-(4-hydroxycinnamoyl)-methane] (FHM) and [bis-(4-hydroxycinnamoyl)-methane] (BHM) and their derivatives, have high antiinflammatory activity against carrageenin-induced rat paw oedema. Curcumin is also effective in formalin induced arthritis. Curcumin reduces intestinal gas formation and carbon tetrachloride and D-galactosamineinduced glutamate oxaloacetate transaminase and glutamate pyruvate transaminase levels. It also increases bile secretion in anaesthetized dogs and rats, and elevates the activity of pancreatic lipase, amylase, trypsin and chymotrypsin.
Curcumin protects isoproterenol-induced myocardial infarction in rats. Curcumin, FHM and BHM also
have anticoagulant activity. Curcumin and an etherextract of C. longa have hypolipemic action in rats and
lower cholesterol, fatty acids and triglycerides in alcohol induced toxicity. Curcumin is also reported to have antibacterial, antiamoebic and antiHIV activities. Curcumin also shows antioxidant activity. It also shows antitumour and anticarcinogenic activities. The volatile oil of C. longa shows antiinflammatory, antibacterial
and antifungal activities. The petroleum ether extract of C. longa is reported to have antiinflammatory activity. Petroleum ether and aqueous extracts have 100% antifertility effects in rats. Fifty per cent ethanolic extract of C.longa shows hypolipemic action in rats. Ethanolic extract also possesses antitumour activity. Alcoholic extract and sodium curcuminate can also offer antibacterial activity. The crude ether and chloroform extracts of C. longa stem are also reported to have antifungal effects. A C. longa fraction containing ar-turmerone has potent antivenom activity.
Pharmacological action of curcumin
Effect on gastrointestinal system
Stomach: Turmeric powder has beneficial effect on the stomach. It increases mucin secretion in rabbits and may thus act as gastroprotectant against irritants. However, controversy exists regarding antiulcer activity of curcumin. Both antiulcer49 and ulcerogenic effects of curcumin have been reported but detailed studies are still lacking. Curcumin has been shown to protect the stomach from ulcerogenic effects of phenylbutazone in guinea pigs at 50 mg/kg dose. It also protects from 5-hydroxytryptamine-induced ulceration at 20 mg/kg dose. However, when 0.5% curcumin was used, it failed to protect against
histamine-induced ulcers. In fact, at higher doses of 50 mg/kg and 100 mg/kg, it produces ulcers in rats. Though the mechanism is not yet clear, an increase in the gastric acid and/or pepsin secretion and reduction in mucin content have been implicated in the induction of gastric ulcer. Recent studies in our laboratory indicate that curcumin can block indomethacin, ethanol and stress-induced gastric ulcer
and can also prevent pylorus-ligation-induced acid secretion in rats. The antiulcer effect is mediated by scavenging of reactive oxygen species by curcumin (unpublished observation).
Intestine: Curcumin has some good effects on the intestine also. Antispasmodic activity of sodium curcuminate was observed in isolated guinea pig ileum. Antiflatulent activity was also observed in both in vivo and in vitro experiments in rats. Curcumin also enhances intestinal lipase, sucrase and maltase activity.
Liver: Curcumin and its analogues have protective activity in cultured rat hepatocytes against carbon tetrachloride, D-galactosamine, peroxide and ionophore-induced toxicity. Curcumin also protects against diethylnitrosamine and 2-acetylaminofluorine-induced altered hepatic foci development58. Increased bile production was reported in dogs by both curcumin and essential oil of C. longa.
Pancreas: 1-phenyl-1-hydroxy-n-pentane, a synthetic derivative of p-tolylmethylcarbinol (an ingredient of C. longa) increases plasma secretion and bicarbonate levels60. Curcumin also increases the activity of pancreatic lipase, amylase, trypsin and chymotrypsin.
Effect on cardiovascular system
Curcumin decreases the severity of pathological changes and thus protects from damage caused by myocardial infarction. Curcumin improves Ca2+-transport and its slippage from the cardiac muscle sarcoplasmic reticulum, thereby raising the possibility of pharmacological interventions to correct the defective Ca2+ homeostasis in the cardiac muscle. Curcumin has significant hypocholesteremic effect in hypercholesteremic rats.
Effect on nervous system
Curcumin and manganese complex of curcumin offer protective action against vascular dementia by exerting antioxidant activity.
Effect on lipid metabolism
Curcumin reduces low density lipoprotein and very low density lipoprotein significantly in plasma and total cholesterol level in liver alongwith an increase of a-tocopherol level in rat plasma, suggesting in vivo interaction between curcumin and a-tocopherol that may increase the bioavailability of vitamin E and decrease cholesterol levels. Curcumin binds with egg and soy-phosphatidylcholine, which in turn binds divalent metal ions to offer antioxidant activity. The increase in fatty acid content after ethanol-induced
liver damage is significantly decreased by curcumin treatment and arachidonic acid level is increased.
Anti-inflammatory activity
Curcumin is effective against carrageenin-induced oedema in rats and mice. The natural analogues of curcumin, viz. FHM and BHM, are also potent antiinflammatory agents. The volatile oil and also the petroleum ether, alcohol and water extracts of C. longa show antiinflammatory effects. The antirheumatic activity of curcumin has also been established in patients who showed significant improvement of symptoms after administration of curcumin. That curcumin stimulates stress-induced expression of stress proteins and may act in a way similar to indomethacin and salicylate, has recently been reported. Curcumin offers antiinflammatory effect through inhibition of NFkB activation. Curcumin has also been shown to reduce the TNF-a-induced expression of the tissue factor gene in bovine aortic-endothelial cells by repressing activation of both AP-1 and NFkB. The antiinflammatory role of curcumin is also mediated through downregulation of cyclooxygenase-2 and inducible nitric oxide synthetase through suppression of NFkB activation. Curcumin also enhances wound-healing in diabetic rats and mice, and in H2O2-induced damage in human keratinocytes and fibroblasts.
Antioxidant effect
The antioxidant activity of curcumin was reported as early as 1975. It acts as a scavenger of oxygen free radicals. It can protect haemoglobin from oxidation. In vitro, curcumin can significantly inhibit the generation of reactive oxygen species (ROS) like superoxide anions, H2O2 and nitrite radical generation by activated macrophages, which play an important role in inflammation. Curcumin also lowers the production of ROS in vivo. Its derivatives, demethoxycurcumin and bis-demethoxycurcumin also have antioxidant effect. Curcumin exerts powerful inhibitory effect against H2O2-induced damage in human keratinocytes and fibroblasts and in NG 108-15 cells. Curcumin reduces oxidized proteins in amyloid pathology in Alzheimer transgenic mice. It also decreases lipid peroxidation in rat liver microsomes, erythrocyte membranes and brain homogenates. This is brought about by maintaining the activities of antioxidant enzymes like superoxide dismutase, catalase and glutathione peroxidase. Recently, we have observed that curcumin prevents oxidative damage during indomethacin-induced gastric lesion not only by blocking inactivation of gastric peroxidase, but also by direct scavenging of H2O2 and ·OH (unpublished observation). Since ROS have been implicated in the development of various pathological conditions, curcumin has the potential to control these diseases through its potent antioxidant activity. Contradictory to the above-mentioned antioxidant effect, curcumin has pro-oxidant activity. Kelly et al. reported that curcumin not only failed to prevent single-strand DNA breaks by H2O2, but also caused DNA damage. As this damage was prevented by antioxidant a-tocopherol, the pro-oxidant role of curcumin has been proved. Curcumin also causes oxidative damage of rat hepatocytes by oxidizing glutathione and of human erythrocyte by oxidizing oxyhaemoglobin, thereby causing haemolysis. The prooxidant activity appears to be mediated through generation of phenoxyl radical of curcumin by peroxidase–H2O2 system, which cooxidizes cellular glutathione or NADH, accompanied by O2 uptake to form ROS. The antioxidant mechanism of curcumin is attributed to its unique conjugated structure, which includes two methoxylated phenols and an enol form of b-diketone; the structure shows typical radical-trapping ability as a chain-breaking antioxidant. Generally, the nonenzymatic antioxidant process of the phenolic material is thought to be mediated through the following two stages:
S-OO° + AH ® SOOH + A° ,
A· + X· ® Nonradical materials,
where S is the substance oxidized, AH is the phenolic antioxidant,
A· is the antioxidant radical and X· is another radical species or the same species as A· . A· and X·
dimerize to form the non-radical product.
Masuda et al. further studied the antioxidant mechanism of curcumin using linoleate as an oxidizable polyunsaturated lipid and proposed that the mechanism involves oxidative coupling reaction at the 3¢position of the curcumin with the lipid and a subsequent intramolecular Diels–Alder reaction.
Anticarcinogenic effect – induction of apoptosis
Curcumin acts as a potent anticarcinogenic compound. Among various mechanisms, induction of apoptosis plays an important role in its anticarcinogenic effect. It induces apoptosis and inhibits cell-cycle progression, both of which are instrumental in preventing cancerous cell growth in rat aortic smooth muscle cells. The antiproliferative effect is mediated partly through inhibition of protein tyrosine kinase and c-myc mRNA expression and the apoptotic effect may partly be mediated through inhibition of protein tyrosine kinase, protein kinase C, c-myc mRNA expression and bcl-2 mRNA expression. Curcumin induces apoptotic cell death by DNA-damage in human cancer cell lines, TK-10, MCF-7 and UACC-62 by acting as topoisomerase II poison. Recently, curcumin has been shown to cause apoptosis in mouse neuro 2a cells by impairing the ubiquitin–proteasome system through the mitochondrial pathway. Curcumin causes rapid decrease in mitochondrial membrane potential and release of cytochrome c to activate caspase
9 and caspase 3 for apoptotic cell death93. Recently, an interesting observation was made regarding curcumin-induced apoptosis in human colon cancer cell and role of heat shock proteins (hsp) thereon. In this study, SW480 cells were transfected with hsp 70 cDNA in either the sense or antisense orientation and stable clones were selected and tested for their sensitivity to curcumin. Curcumin was found to be ineffective to cause apoptosis in cells having hsp 70, while cells harbouring antisense hsp 70 were highly sensitive to apoptosis by curcumin as measured by nuclear condensation, mitochondrial transmembrane potential, release of cytochrome c, activation of caspase 3 and caspase 9 and other parameters for apoptosis. Expression of glutathione S-transferase P1-1 (GSTP1-1) is correlated to carcinogenesis and curcumin has been shown to induce apoptosis in K562 leukaemia cells by inhibiting the expression
of GSTP1-1 at transcription level95. The mechanism of curcumin-induced apoptosis has also been studied in Caki cells, where curcumin causes apoptosis through downregulation of Bcl-XL and IAP, release of cytochrome c and inhibition of Akt, which are markedly blocked by Nacetylcysteine, indicating a role of ROS in curcumin induced cell death. In LNCaP prostrate cancer cells, curcumin induces apoptosis by enhancing tumour necrosis factor-related apoptosis-inducing ligand (TRAIL). The combined treatment of the cell with curcumin and TRAIL induces DNA fragmentation, cleavage of procaspase 3, 8 and 9, truncation of Bid and release of cytochrome c from mitochondria, indicating involvement of both external receptor-mediated and internal chemical-induced apoptosis in these cells. In colorectal carcinoma cell line, curcumin delays apoptosis along with the arrest of cell cycle at G1 phase. Curcumin also reduces P53 gene expression, which is accompanied with the induction of HSP-70 gene through initial depletion of intracellular Ca2+. Curcumin also produces nonselective inhibition of proliferation in several leukaemia, nontransformed haematopoietic progenitor cells and fibroblast cell lines. That curcumin induces apoptosis and large-scale DNA fragmentation has also been observed in Vg9Vd2+ T cells through inhibition of isopentenyl pyrophosphate-induced NFkB activation, proliferation and chemokine production. Curcumin induces apoptosis in human leukaemia HL-60 cells, which is blocked by some antioxidants. Colon carcinoma is also prevented by curcumin through arrest of cell-cycle progression independent of inhibition of prostaglandin synthesis. Curcumin suppresses human breast carcinoma through multiple pathways. Its antiproliferative effect is estrogendependent in ER (estrogen receptor)-positive MCF-7 cells and estrogen-independent in ER-negative MDA-MB-231 cells. Curcumin also downregulates matrix metalloproteinase (MMP)-2 and upregulates tissue inhibitor of metalloproteinase (TIMP)-1, two common effector molecules involved in cell invasion. It also induces apoptosis through P53-dependent Bax induction in human breast cancer cells. However, curcumin affects different cell lines differently. Whereas leukaemia, breast, colon, hepatocellular and ovarian carcinoma cells undergo apoptosis in the presence of curcumin, lung, prostate, kidney, cervix and CNS malignancies and melanoma cells show resistance to cytotoxic effect of curcumin.
Curcumin also suppresses tumour growth through various pathways. Nitric oxide (NO) and its derivatives play a major role in tumour promotion. Curcumin inhibits iNOS and COX-2 production69 by suppression of NFkB activation. Curcumin also increases NO production in NK cells after prolonged treatment, culminating in a stronger tumouricidal effect. Curcumin also induces apoptosis in AK-5 tumour cells through upregulation of caspase-3. Reports also exist indicating that curcumin blocks dexamethasoneinduced
apoptosis of rat thymocytes. Recently, in Jurkat cells, curcumin has been shown to prevent glutathione
depletion, thus protecting cells from caspase-3 activation and oligonucleosomal DNA fragmentation. Curcumin also inhibits proliferation of rat thymocytes. These strongly imply that cell growth and cell death share a common pathway at some point and that curcumin affects a common step, presumably involving modulation of AP-1 transcription factor.
Pro/antimutagenic activity
Curcumin exerts both pro- and antimutagenic effects. At 100 and 200 mg/kg body wt doses, curcumin has been shown to reduce the number of aberrant cells in cyclophosphamide-induced chromosomal aberration in Wistar rats. Turmeric also prevents mutation in urethane (a powerful mutagen) models. Contradictory reports also exist. Curcumin and turmeric enhance g-radiation-induced chromosome aberration in Chinese hamster ovary. Curcumin has also been shown to be non-protective against
hexavalent chromium-induced DNA strand break. In fact, the total effect of chromium and curcumin is additive in causing DNA breaks in human lymphocytes and gastric mucosal cells
Anticoagulant activity
Curcumin shows anticoagulant activity by inhibiting collagen and adrenaline-induced platelet aggregation in vitro as well as in vivo in rat thoracic aorta.
Antifertility activity
Petroleum ether and aqueous extracts of turmeric rhizomes show 100% antifertility effect in rats when fed orally. Implantation is completely inhibited by these extracts. Curcumin inhibits 5a-reductase, which converts testosterone to 5a-dihydrotestosterone, thereby inhibiting the growth of flank organs in hamster. Curcumin also inhibits human sperm motility and has the potential for the development of a novel intravaginal contraceptive.
Antidiabetic effect
Curcumin prevents galactose-induced cataract formation at very low doses. Both turmeric and curcumin decrease blood sugar level in alloxan-induced diabetes in rat. Curcumin also decreases advanced glycation end products induced complications in diabetes mellitus.
Antibacterial activity
Both curcumin and the oil fraction suppress growth of several bacteria like Streptococcus, Staphylococcus, Lactobacillus, etc. The aqueous extract of turmeric rhizomes has antibacterial effects. Curcumin also prevents growth of Helicobacter pylori CagA+ strains in vitro.
Antifungal effect
Ether and chloroform extracts and oil of C. longa have antifungal effects. Crude ethanol extract also possesses antifungal activity. Turmeric oil is also active against Aspergillus flavus, A. parasiticus, Fusarium moniliforme and Penicillium digitatum.
Antiprotozoan activity
The ethanol extract of the rhizomes has anti-Entamoeba histolytica activity. Curcumin has anti-Leishmania activity in vitro. Several synthetic derivatives of curcumin have anti-L. amazonensis effect. Anti-Plasmodium falciparum and anti-L. major effects of curcumin have also been reported.
Antiviral effect
Curcumin has been shown to have antiviral activity. It acts as an efficient inhibitor of Epstein-Barr virus (EBV) key activator Bam H fragment z left frame 1 (BZLF1) protein transcription in Raji DR-LUC cells. EBV inducers such as 12-0-tetradecanoylphorbol-13-acetate, sodium butyrate and transforming growth factor-beta increase the level of BZLF1 m-RNA at 12–48 h after treatment in these cells, which is effectively blocked by curcumin. Most importantly, curcumin also shows anti-HIV (human immunodeficiency
virus) activity by inhibiting the HIV-1 integrase needed for viral replication. It also inhibits UV lightinduced
HIV gene expression. Thus curcumin and its analogues may have the potential for novel drug development
against HIV.
Antifibrotic effect
Curcumin suppresses bleomycin-induced pulmonary fibrosis in rats. Oral administration of curcumin at 300 mg/kg dose inhibits bleomycin-induced increase in total cell counts and biomarkers of inflammatory responses. It also suppresses bleomycin-induced alveolar macrophage-production of TNF-a, superoxide and nitric oxide. Thus curcumin acts as a potent antiinflammatory and antifibrotic agent.
Antivenom effect
Ar-turmerone, isolated from C. longa, neutralizes both haemorrhagic activity of Bothrops venom and 70% lethal effect of Crotalus venom in mice4. It acts as an enzymatic inhibitor of venom enzymes with proteolytic activities.
Pharmacokinetic studies on curcumin
Curcumin, when given orally or intraperitoneally to rats, is mostly egested in the faeces and only a little in the urine. Only traces of curcumin are found in the blood from the heart, liver and kidney. Curcumin, when added to isolated hepatocytes, is quickly metabolized and the major biliary metabolites are glucuronides of tetrahydrocurcumin and hexahydrocurcumin. Curcumin, after metabolism in the liver, is mainly excreted through bile.
Clinical studies and medicinal applications of turmeric and curcumin
Although various studies have been carried out with turmeric extracts and some of its ingredients in several animal models, only a few clinical studies are reported so far.
Turmeric
Powdered rhizome is used to treat wounds, bruises, inflamed joints and sprains in Nepal. In current traditional Indian medicine, it is used for the treatment of biliary disorders, anorexia, cough, diabetic wounds, hepatic disorders, rheumatism and sinusitis. Data are also available showing that the powder, when applied as capsules to patients with respiratory disease, gives relief from symptoms like dyspnoea, cough and sputum. A short clinical trial in patients with definite rheumatoid arthritis showed significant
improvement in morning stiffness and joint swelling after two weeks of therapy with oral doses of 120 mg/
day. Application of the powder in combination with other plant products is also reported for purification of blood and for menstrual and abdominal problems.
Curcumin
In patients undergoing surgery, oral application of curcumin reduces post-operative inflammation. Recently, curcumin has been formulated as slow-release biodegradable microspheres for the treatment of inflammation in arthritic rats. It is evident from the study that curcumin biodegradable microspheres could be successfully employed for therapeutic management of inflammation.
Future prospects
Turmeric has been used in ayurvedic medicine since ancient times, with various biological applications. Although some work has been done on the possible medicinal applications, no studies for drug development have been carried out as yet. Although the crude extract has numerous medicinal applications, clinical applications can be made only after extensive research on its bioactivity, mechanism
of action, pharmacotherapeutics and toxicity studies. However, as curcumin is now available in pure form, which shows a wide spectrum of biological activities, it would be easier to develop new drugs from this compound after extensive studies on its mechanism of action and pharmacological effects. Recent years have seen an increased enthusiasm in treating various diseases with natural products. Curcumin is a non toxic, highly promising natural antioxidant compound having a wide spectrum of biological functions. It is expected that curcumin may find application as a novel drug in the near future to control various diseases, including inflammatory disorders, carcinogenesis and oxidative stress-induced pathogenesis.
Source: Review Articles, Current Science.
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