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Turmeric

Turmeric can be used for rheumatoid arthritis (curcumin), osteoarthritis (in combination), dyspepsia, inflammatory conditions such as asthma, infections, eczema, psoriasis, long-term prevention and treatment of cardiovascular disease, adjunct in the treatment of hyperlipidaemia. It can also be used for  prevention of cancer and adjunct to cancer treatment, to improve gastric and hepatic function, as an antioxidant, poor digestion and liver function. Topically for inflammations, skin diseases, skin infections, treatment of cancerous lesions (in an uncontrolled trial).

Publisert: 16.03.2014 - Endret: 16.03.2014

Synonyms

Curcuma domestica Val. (botanical synonym), Indian saffron (Engl), Kurkumawurzelstock, Gelbwurzel (Ger), rhizome de curcuma, safran des Indes (Fr), gurkemeje (Dan), jianghuang (Chin), shati (Sanskrit).

What is it?

The rhizome of Curcuma longa L. (turmeric) has been used as a medicine, spice and colouring agent for thousands of years. A native of India and South-East Asia, it is now cultivated in many countries but India still accounts for a large percentage of current world production. Turmeric was listed in an Assyrian herbal dating from about 600 BC and was also mentioned by Dioscorides.

Effects/actions

Effects

Antiinflammatory (curcumin is a dual inhibitor of arachidonic acid metabolism); antioxidant (particularly by reducing lipid peroxidation); favourably influences cardiovascular function; antimicrobial (particularly by topical application); inhibits carcinogenesis and tumour promotion.

Traditional view

In India, turmeric is regarded as a stomachic, tonic and blood purifiers which is used for poor digestion, fevers, skin conditions, vomiting in pregnancy and liver disorders. Externally, it is used for conjunctivitis, skin infections, cancer, sprains, arthritis, haemorrhoids and eczema.1,2 Indian women apply it to the skin to reduce hair growth.3

In China different uses are attributed to the `rhizome` and `tuber`. Turmeric `rhizome` is said to be a Blood and Qi (vital energy) stimulant with analgesic properties. It is used to treat chest and abdominal pain and distension, jaundice, frozen shoulder, amenorrhoea due to blood stasis and postpartum abdominal pain due to stasis. It is also used for wounds and injuries.4 The `tuber` has similar properties but is used in hot conditions as it is more cooling and has been used to treat viral hepatitis.5

In Western herbal medicine, turmeric was regarded as an aromatic digestive stimulant and as a cure for jaundice.6

Use

Can be used for

Rheumatoid arthritis (curcumin), osteoarthritis (in combination); dyspepsia; topical treatment of cancerous lesions (in an uncontrolled trial).

Topically for skin disorders; internal use for poor digestion and liver function.

Inflammatory conditions such as asthma, infections, eczema, psoriasis; long-term prevention and treatment of cardiovascular disease, adjunct in the treatment of hyperlipidaemia; prevention of cancer and adjunct to cancer treatment; to improve gastric and hepatic function; as an antioxidant. Topically for inflammations, skin diseases and skin infections.

Dosage

Turmeric should be taken as the powdered rhizome or the 1:1 liquid extract prepared using 45% ethanol or higher. The dose for the liquid extract is 5-14 ml per day which is best taken in 4-5 equal doses throughout the day. A heaped teaspoon of powdered turmeric (about 4 g) can be mixed with water to a slurry and drunk 1-2 times daily. A teaspoon of lecithin can be added to improve absorption. Taking turmeric as a powder may be more desirable for antiinflammatory effects, since aqueous extracts devoid of essential oil or curcumin also show significant activity. Turmeric extracts should be stored in dark glass away from direct sunlight due to the decomposition of curcumin on exposure to light.

Duration of use

May be taken in the long term within the recommended dosage.

Use in pregnancy and lactation

No adverse effects expected at the recommended dosage.

Effects on ability to drive and operate machines

None known.

Side effects

Turmeric at 10% of diet caused some hair loss in rats and may have this effect in humans.133 A case of allergic contact dermatitis to turmeric in a spice shop worker was reported.3 The authors concluded that turmeric is probably a weak sensitizer and is not a common cause of allergic contact dermatitis.

Overdose

Not known.

Interactions

High doses should not be given to patients taking antiplatelet or anticoagulant drugs.

Contraindications

There are no contraindications for turmeric other than allergic reaction, which is probably rare. According to the Commission E, turmeric is contraindicated where there is obstruction of the biliary tract and should be used only after seeking professional advice if gallstones are present.132

Special warnings and precautions

High doses should not be given to patients taking antiplatelet or anticoagulant drugs and care should be exercised with women who wish to conceive or patients complaining of hair loss. Patients applying topical doses should be cautioned against excessive exposure to sunlight.

Regulations

Current regulatory status in selected countries

Turmeric is official in the Pharmacopoeia of the People`s Republic of China (English Edition, 1997). It was official in the second edition of the Indian Pharmacopoeia (1966) but was not included in the third edition (1985).

Turmeric is covered by a positive Commission E monograph and can be used for the treatment of dyspeptic conditions.

Turmeric is not on the UK General Sale List.

Turmeric and turmeric oleoresin have GRAS status. It is also freely available as a `dietary supplement` in the USA under DSHEA legislation (1994 Dietary Supplement Health and Education Act).

Turmeric is not included in Part 4 of Schedule 4 of the Therapeutic Goods Act Regulations of Australia.

Legal Category (Licensed Products)

Claim

Pharmacopoeial and other monographs

Extended info

Technical data

Botany

Turmeric, a member of the Zingiberaceae (ginger) family, is a perennial herb growing up to 1 m high with large tufted leaves. The leaf blade is long and tapers to the base. Pale yellow flowers containing three petals appear close to ground level. The rhizome is oblong or cylindrical and often short-branched. The external colour of the rhizome is brown and internally ranges from yellow to yellow orange.7,8 The rhizome consists of two parts: an egg-shaped primary rhizome and several cylindrical and branched secondary rhizomes growing from the primary rhizome. These two parts were once differentiated in the Western trade as C. rotunda and C. longa.9 In traditional Chinese medicine this differentiation is retained, the primary rhizome being called the `tuber` and the secondary rhizome, the `rhizome`.5

Turmeric rhizome

Part(s) used

Dried secondary rhizome (containing not less than 3% curcuminoids calculated as curcumin and not less than 3% volatile oil, calculated on dry-weight basis).

Key constituents

Essential oil (3-5%), containing sesquiterpene ketones (65% including ar-turmerone), zingiberene (25%), phellandrene, sabinene, cineole, borneol.10

Yellow pigments (3-6%) known as diarylheptanoids, including curcumin and methoxylated curcumins.10,11

 

ar-Turmerone                                                  Diarylheptanoids

Preparations

Dried root as a decoction, liquid extract; oleoresin or essential oil for internal or external use. The powdered root is also used externally.

Non-clinical data

Pharmacodynamics

The clinical relevance of in vitro pharmacological studies on curcumin (or where it was administered by injection) is uncertain, especially in the context of oral (but not topical) use of turmeric. This is because curcumin appears to undergo rapid biotransformation during and after gastrointestinal absorption (see also the Pharmacokinetics section). The biotransformation products of curcumin need to be identified and studied, since oral doses of curcumin do appear to exert significant pharmacological activity in several experimental and clinical models.

Antiinflammatory activity of curcumin

The antiinflammatory activity of curcumin was first reported in 1971.12 In an extension of this work,13 it was reported that oral doses of curcumin possess significant antiinflammatory action in both acute and chronic animal models. Curcumin was as potent as phenylbutazone and almost as potent as cortisone in the acute test (carrageenan oedema) but only about half as potent as phenylbutazone in chronic tests.

Slaked lime is traditionally mixed with powdered turmeric for topical application as an antiinflammatory agent.14 This process probably increases the water-solubility of curcumin through salt formation. The antiinflammatory action of sodium curcuminate was investigated in rats as an experimental model of this traditional use.15 Sodium curcuminate exhibited considerably higher antiinflammatory activity than either curcumin or hydrocortisone in acute and chronic tests. This was confirmed in a later study, which also found that curcumin and sodium curcuminate were more potent than phenylbutazone in acute and chronic models.16 However, curcumin was only one-tenth as active as ibuprofen in reducing subacute inflammation.17

NSAIDs such as phenylbutazone can cause gastric ulceration. Curcumin was found to have a lower ulcerogenic index (0.60) than a nearly equivalent active dose of phenylbutazone (1.70).13 However, curcumin given orally for 6 consecutive days to rats caused gastric ulceration at a dose of 100 mg/kg but not at a dose of 50 mg/kg.18 In contrast, lower doses of curcumin in guinea pigs protected against gastric ulceration from phenylbutazone19 but not histamine.20 Ulceration caused by high doses of cur-cumin is associated with a marked reduction in mucin secretion.18

The mode of action of curcumin is not fully understood. Curcumin potently inhibited leukotriene production from intact neutrophils and at higher concentrations also inhibited prostaglandin production from bovine seminal vesicles.21 Curcumin also inhibited the production of leukotrienes and prostaglandins from mouse epidermal microsomes.22 Thus curcumin is a dual inhibitor of arachidonic acid (AA) metabolism in that it inhibits both the enzymes 5-lipoxygenase and cyclooxygenase. Dual inhibitors of AA metabolism are attracting interest as antiinflammatory agents since they prevent the potentially damaging effects of increased leukotriene production which can result from the use of only cyclooxygenase inhibitors such as aspirin. Moreover, leukotrienes may play an important role in some inflammatory processes. Curcumin is probably only a mild inhibitor of cyclooxygenase in vivo since, unlike aspirin and phenylbutazone, it lacks analgesic and antipyretic activities.13 Even the more potent sodium curcuminate does not demonstrate analgesic and antipyretic effects.16

Curcumin inhibited the 5-lipoxygenase activity in rat peritoneal neutrophils as well as the 12-lipoxygenase and the cyclooxygenase activities in human platelets. In a cell-free peroxidation system, curcumin exerted strong antioxidant activity. Hence its effects on these dioxygenases are probably due to its reducing (antioxidant) capacity.23

Curcumin may also possess an indirect antiinflammatory activity via the adrenal cortex although results are conflicting. Curcumin was less effective in adrenalectomized rats,13 whereas sodium curcuminate maintained its activity.16 A single dose of sodium curcuminate did not alter plasma cortisol levels16 but prolonged doses of curcumin doubled plasma cortisol.17 It is possible that curcumin and sodium curcuminate may be acting via different mechanisms.

Curcumin was more potent than ibuprofen as a stabilizer of liver lysosomal membranes and was also active as an uncoupler of oxidative phosphorylation.17 Recently it was found that curcumin inhibits aggregation, degranulation and superoxide generation from neutrophils in vitro.24 It was concluded that at least part of the antiinflammatory action of curcumin is mediated via inhibition of neutrophil function.

Antiinflammatory activity of turmeric extracts and essential oil

Injected doses of the petroleum ether extract of turmeric, and two fractions isolated from it, demonstrated significant antiinflammatory activity when compared to hydrocortisone and phenylbutazone in acute and chronic tests.25 Successive extraction of turmeric with petroleum ether followed by 50% alcohol and then water gave yields of 2%, 9% and 10% respectively.26 These fractions, representing 21% by weight of the components of turmeric, were then compared for antiinflammatory activity. In both acute and chronic tests the aqueous extract was significantly more active and was often more active than reference drugs such as hydrocortisone and oxyphenbutazone. Unfortunately no fraction was chemically characterized and doses were administered by intraperitoneal injection, both factors which make the relevance of these findings to the action of oral doses of turmeric difficult to interpret.

Topical application of aqueous extracts of turmeric delayed corneal wound healing in rabbits indicative of `cortisone-like` antiinflammatory activity.27 An aqueous-alcoholic extract was inactive but this corresponded to a much lower dose of turmeric. Since curcumin is relatively insoluble in water this local `cortisone-like` effect must be due to other components of turmeric.

A diethyl ether extract of turmeric inhibited platelet aggregation and altered eicosanoid biosynthesis in human platelets (see below)28 This research suggests that turmeric may have antiinflammatory activity partly due to its inhibition of AA uptake and release from membrane phospholipids.

Oral doses of the essential oil of turmeric were studied in adjuvant arthritis in rats 29 Significant antiinflammatory activity was found in this long-term test at doses of 0.1 ml/kg. The essential oil also has antihistaminic properties,30 which may explain the antiinflammatory effect observed in a short-term test.29

Antiplatelet activity

Agents which cause a relative inhibition of platelet aggregation may be useful in the prevention and treatment of cardiovascular degeneration. Sodium curcuminate had no effect on in vitro platelet aggregation stimulated by ADP, epinephrine or ,collagen.16 However, curcumin inhibited ADP-, collagen- and epinephrine-induced platelet aggregation in vitro and ex vivo with about the same activity as aspirin.31 Unlike aspirin, curcumin did not decrease prostacyclin synthesis in rat thoracic aorta. The suggestion that curcumin selectively inhibits thromboxane production was supported by a contemporary publication.32 In this study curcumin was found to inhibit thromboxane production from platelets in vitro and ex vivo. Also, it was found that increasing doses of curcumin progressively protected against collagen- or epinephrine-induced thrombosis in mice, whereas increasing doses of aspirin beyond a certain level afforded decreased protection. This again suggests a thromboxane-inhibiting but prostacyclin-sparing activity for curcumin.

A recent study found that curcumin inhibited platelet aggregation induced by arachidonate, adrenalin and collagen. Curcumin inhibited thromboxane B2 production from exogenous radiolabelled arachidonate in washed platelets with a concomitant increase in the formation of 12-lipoxygenase products. It inhibited the incorporation of arachidonate into platelet phospholipids and inhibited the liberation of free arachidonic acid.33

A diethyl ether extract of turmeric inhibited AA-but not ADP- and collagen-induced platelet aggregation in vitro and also inhibited thromboxane production from exogenous AA in washed platelets.28 The turmeric extract also inhibited incorporation of AA into platelet phospholipids and AA release under appropriate stimulation. The chemical content of the diethyl ether extract was not investigated. The author noted that a low incidence of cardiovascular disease is observed in the regions where spices such as turmeric are regularly consumed. Chinese research found that turmeric extract and curcumin enhanced fibrinolytic activity and inhibited platelet aggregation but the essential oil was devoid of these activities.4

Antioxidant activity

Curcumin inhibited in vitro lipid peroxide formation in liver homogenates from oedemic mice.12 Curcumin is also an in vitro inhibitor of lipid peroxidation in brain tissue.34 Lipid peroxidation induced by air on linoleic acid was inhibited by curcumin and related diarylheptanoids extracted from turmeric.35 These natural curcuminoids also inhibited haemolysis and lipid peroxidation of mouse erythrocytes induced by hydrogen peroxide but were not as active as vitamin E.36 Curcumin has a weaker scavenging effect than vitamin C on active oxygen radicals generated by polymorphonuclear leucocytes but is stronger than vitamin E.37 However, curcumin had the strongest scavenging effect on hydroxyl radicals.

Curcumin was as effective as the antioxidant BHA in inhibiting lipid peroxidation.38 Curcumin protected DNA against single-strand breaks induced by singlet oxygen. The observed antioxidant activity was both time and dose dependent. The protective ability of cur-cumin was higher than that of lipoate, alpha-tocopherol and beta-carotene.39 Curcumin reduced experimentally generated nitrite in vitro. This nitric oxide-scavenging activity was also exhibited by other curcuminoids.40

An aqueous extract of turmeric was also found to be an effective inhibitor of oxidation. This unidentified water-soluble antioxidant from turmeric extended 80% protection to DNA against peroxidative injury and has potential as an antipromoter. The active component may have been an antioxidant protein, which has recently been isolated.41 However, this constituent probably does not account for the in vivo antioxidant activity of turmeric since it would not be present in ethanolic extracts and is probably not absorbed after oral doses.

The efficacy of curcumin in preventing cataract formation was tested ex vivo in a rat model. Lenses from curcumin-treated rats were much more resistant to oxidant-induced opacification than were lenses from control animals.42 Oral administration of curcumin reduced iron-induced hepatic damage in rats by lowering lipid peroxidation.43 Dietary turmeric (1%) lowered lipid peroxidation in rats compared to controls by enhancing the activities of antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase).44

Curcumin completely inhibited the superoxide anion hydrogen peroxide and nitrite radical production ex vivo by rat peritoneal macrophages. Capsaicin and curcumin were fed to rats on a diet containing 8% by weight of coconut oil, olive oil, peanut oil or cod liver oil for 8 weeks. Macrophages isolated from these animals produced lower levels of reactive oxygen species (ROS) compared to the macrophages from the control groups fed the oil alone.45 Turmeric ethanolic extract administered orally to mice (4 mg/kg/day) for 4 weeks resulted in a decrease in levels of both plasma and liver lipid peroxides, compared to controls.46 Turmeric extract (equivalent to 20 mg curcumin/day) for 45 days dramatically decreased blood lipid peroxide levels in an uncontrolled study on 18 healthy males.47

Hypolipidaemic activity

Toxicity studies on rats to establish the safety of turmeric extracts as a colouring agent also found that liver levels of total cholesterol were somewhat lower than normal.48 A subsequent study revealed that turmeric extract and curcumin counteracted the increase in liver cholesterol in rats induced by cholesterol feeding.49

Dietary levels of curcumin as low as 0.1% significantly reduced the rises in serum and liver cholesterol in rats fed cholesterol but did not lower serum cholesterol in rats fed a normal diet.50 It was also found that curcumin increased faecal excretion of bile acids and cholesterol in both the normal and hypercholesterolaemic rats and counteracted the rise in body and liver weights caused by cholesterol intake. These findings would suggest that turmeric might raise the ratio of HDL-cholesterol to total cholesterol and this was verified in a subsequent study on hyperlipidaemic rats.51 Triglyceride levels were also significantly lower with turmeric treatment. Turmeric and curcumin had no effect on cholesterol levels of plasma, liver or egg yolk in hens fed a diet containing cholesterol.52

The activity of hepatic cholesterol-7-alpha-hydrolase (the rate-limiting enzyme of bile acid biosynthesis) was significantly elevated in rats fed cur-cumin. Serum and liver microsomal cholesterol contents were also significantly higher. However, the simultaneous stimulation of cholesterol synthesis by curcumin suggests that this may not be the mechanism for its hypocholesterolaemic action, which may be solely due to interference with exogenous cholesterol absorption.53

In experimentally induced diabetic rats maintained on a 0.5% curcumin-containing diet for 8 weeks, blood cholesterol was lowered significantly, exclusively from the LDL-VLDL fraction. Significant decreases in blood triglyceride and phospholipids were also observed. Hepatic cholesterol-7-alpha-hydroxylase activity was markedly higher, suggesting a higher rate of cholesterol catabolism.54

Effects on the digestive tract

Early research demonstrated that the essential oil of turmeric55 and curcumin56 increased bile secretion. Detailed studies found that while injections of curcumin and essential oil increase bile secretion, the aqueous extract was inactive. Curcumin and the essential oil were each about half as active as sodium deoxycholate administered the same way.57 Investigations of sodium curcuminate found a stimulation of bile flow although the concentration of solids in the bile was somewhat dereased.58 At higher doses total excretion of bile salts, bilirubin and cholesterol was enhanced. Such a finding is consistent with animal feeding experiments with curcumin, which also found increased bile acid and cholesterol excretion.50

Mice with preestablished cholesterol gallstones were fed a diet containing curcumin (0.5%) for 5 or 10 weeks. After 5 weeks, a regression of gallstones occurred in 45% and after 10 weeks in 80% compared to controls. Biliary cholesterol decreased and phospholipids and bile acids increased over the duration of feeding.41 Feeding a lithogenic diet supplemented with 0.5% cur-cumin for 10 weeks reduced the incidence of gallstone formation to 26% when compared to mice fed the litho-genic diet alone. Biliary cholesterol concentration, litho-genic index and the cholesterol/phospholipid ratio of bile were also reduced.59

A test meal of 0.5 g/kg of turmeric in rabbits did not show any change in the volume or acid and pepsin content of gastric secretions but the mucin content was considerably increased, suggestive of a mucus stimulatory effect .60 This contrasts with studies on high doses of cur-cumin which found ulceration associated with a marked decrease in mucin secretion.18 Oral doses of 0.5 g/kg of an ethanolic extract of turmeric produced significant protection against ulceration caused by stress, pyloric ligation, indomethacin and reserpine in rats.61 Turmeric extract increased gastric wall mucus production and also enhanced its cytoprotective quality.

After finding a protective effect for turmeric extract against carbon tetrachloride-induced hepatotoxicity in mice, the various constituents of turmeric were examined for in vitro hepatoprotective activity.62 Curcumin and related diarylheptanoids (curcuminoids) exhibited considerable intrinsic activity; that is, activity was not due to their metabolites.

Antimicrobial activity

An alcoholic extract of turmeric, its essential oil and curcumin inhibited the growth of Gram-positive bacteria in vitro.63 However, the antibacterial activity of turmeric is much weaker than conventional anti-biotics.64 The essential oil of turmeric has significant antifungal activity at dilutions of 1 in 500.65

An interesting recent discovery is that low concentrations of curcumin are highly toxic to Salmonella in the presence of visible light.66 This phototoxic effect was thought to be due to unstable intermediates, probably radicals formed during the irradiation. Since an E. coli strain with DNA repair capacity was largely resistant to curcumin phototoxicity, this implies that light in combination with curcumin is genotoxic and may be mutagenic. The authors concluded that the observed phototoxicity makes curcumin a potential photosensitizing drug which may be useful in the phototherapy of psoriasis, cancer and bacterial and viral infections.

This study was confirmed by other workers who found that curcumin is more phototoxic to Gram-positive bacteria compared to Gram-negative bacteria.67 Oxygen is required for the phototoxicity of curcumin and results were suggestive that hydrogen peroxide might be the toxic intermediate.

Turmeric oil (the hexane extract of the rhizome) at dilutions of 1:40 to 1:320 inhibited 15 isolates of dermatophytes and at dilutions of 1:40 to 1:80 inhibited four isolates of pathogenic fungi in vitro (curcumin was inactive). Six isolates of yeasts were insensitive to turmeric oil and curcumin. Turmeric oil (diluted to 1:80) applied topically on the 7th day following dermatophytosis induction with Trichophyton rubrum in guinea pigs resulted in improvement within 2-5 days after application and the lesion disappeared at days 6-7.68

Cancer prevention

Turmeric and curcumin possess antimutagenic and antipromotion activities which are probably related to the antioxidant and antiinflammatory properties of curcumin. Curcumin showed a dose-dependent decrease in the in vitro mutagenicities of cayenne extract and capsaicin.69 This was comparable to the effect of known antioxidants such as vitamin E. In the presence of liver homogenate, curcumin also inhibited the in vitro mutagenicity of tobacco smoke condensates, tobacco and benzo (alpha) pyrene (BAP) in a dose-dependent manner.70 However, it did not inhibit the mutagenicity of sodium azide and streptozocin, which occurs in the absence of liver homogenate. These results indicate that curcumin may alter the metabolism of those carcinogens which require hepatic microsomal activation.

Curcumin and aqueous extract of turmeric protected against DNA damage in human lymphocytes induced by fuel smoke condensate.71 However, curcumin had no effect on the frequency of mitotic irregularities in virus-transformed cells72 and curcumin feeding did not inhibit BAP-induced nuclear damage to murine intestinal cells in vivo.73 In contrast, turmeric at 1% in the diet of mice reduced BAP-induced stomach tumours and also reduced the incidence of spontaneous mammary tumours.74 A dose-dependent decrease in binding of benzo(alpha)pyrene metabolites to calf thymus DNA was observed in the presence of turmeric, curcumins and aqueous turmeric extract but not in the presence of curcumin-free aqueous turmeric extract. Further studies using mouse liver microsomes indicated that three curcuminoids inhibited benzo(alpha)pyrene-DNA adduct formation.75

Topically applied curcumin potently inhibited DNA synthesis and tumour promotion induced by 12-0-tetradecanoylphorbol-13-acetate (TPA) in mouse skin.76 This effect parallels the inhibitory effect of cur-cumin on TPA-induced epidermal inflammation and also on epidermal lipoxygenase and cyclooxygenase activities.22 In other words, the inhibitory effect of curcumin on tumour promotion is related to its antiinflammatory activity. Repeated applications of turmeric or curcumin in the promotion phase produced a significant reduction in mouse skin papillomas induced by DMBA followed by croton oil promotion.77

It has been demonstrated that turmeric increases the activity of the carcinogen-detoxifying enzyme glutathione-S-transferase in the stomach, liver and oesophagus of mice.78 Glutathione levels were also significantly elevated and the in vivo mutagenic effect of BAP in mouse bone marrow cells was suppressed. Curcumin may be responsible for this activity.79

Curcuminoids and turmeric caused dose-dependent inhibition of nitrosomethylurea formation in vitro.80 Nitrosamines can be formed in cured meats through the reaction of secondary amines with nitrites added during manufacturing and are potent carcinogens.

Curcumin and genistein (a component of soybean) were able to inhibit the growth of oestrogen-positive human breast cells induced individually or by a mixture of pesticides or oestradiol. When curcumin and genistein were added together to the cells, a synergistic effect resulting in a total inhibition of cell induction was observed. It was concluded that inclusion of turmeric and soybeans in the diet may assist in the prevention of breast cancer.81

Recently several in vitro and in vivo studies have confirmed that curcuminoids inhibit cancer at initiation, promotion and progression stages of develop-ment.82 Curcumin is a potent inhibitor of TPA-induced ornithine decarboxylase activity and arachidonic acid-induced inflammation and topically inhibits

TPA-induced tumour promotion in mouse skin. Structurally related compounds such as chlorogenic acid are less potent inhibitors.83 Three curcuminoids from turmeric demonstrated potent inhibition of mutagenesis in vitro and in croton oil-induced tumour promotion. Compared to 90% of control animals, 10% of curcumin III-, 20% of curcumin II- and 40% of curcumin I-treated animals developed papillomas.84

Dietary administration of curcumin to rats significantly inhibited the incidence of colon adenocarcinomas and the multiplicity of invasive and non-invasive tumours. It also significantly suppressed the colon tumour volume by more than 57% compared to the control diet. The chemopreventive action may at least in part be related to the modulation of arachidonic acid metabolism.85 Oral administration of turmeric to mice from 2 months of age caused a suppression of mammary tumour virus-related reverse transcriptase activity and preneoplastic changes in mammary glands. Feeding turmeric from 6 months of age resulted in a 100% inhibition of mammary tumours.86

Catechin in drinking water and dietary turmeric significantly inhibited the tumour burden and tumour incidence in two tumour models: experimentally induced forestomach tumour in mice and oral mucosal tumour in golden hamsters. Chemoprevention utilizing both catechin and dietary turmeric inhibited both the gross tumour yield and burden more effectively in both tumour models than treatment with the individual components.87 Oral administration of curcumin via diet inhibited carcinogen-induced forestomach tumorigenesis, duodenal tumorigenesis and colon tumorigenesis in mice. Curcumin inhibited the number of tumours per mouse, the percentage of mice with tumours and also reduced tumour size. Administration of curcumin during the initiation period resulted in a larger decrease in colon tumour incidence compared to administration during the postinitiation period.88 Turmeric (2% or 5%) in the diet significantly inhibited benzo(alpha)pyreneinduced forestomach tumours in mice and this was dose and time dependent. The 2% diet significantly suppressed skin tumours in mice. The 5% turmeric diet for 7 consecutive days resulted in a 38% decrease in the hepatic cytochrome B-5 and cytochrome P-450 levels. Glutathione content was increased by 12% and glutathione-S-transferase activity was enhanced by 32% in the liver.89

Antitumour activity

A turmeric extract prepared with 50% ethanol inhibited the cell growth of normal mammalian cells and was cytotoxic to lymphoma cells at a concentration of 0.4 mg/mi.90 The active constituent was found to be curcumin which was cytotoxic to lymphoma cells at a concentration of 4 pg/ml. Injections of both turmeric extract and curcumin reduced the development of tumours and enhanced survival in mice injected with lymphoma cells.90 Sodium curcuminate was devoid of cytotoxic activity in vitro.91 Earlier work reported that a turmeric extract exhibited cytotoxicity to mammalian cells in vitro by arresting mitosis and altering chromosome morphology.92 The recently observed cytotoxicity of high concentrations of curcumin to rat hepatocytes was attributed to curcumin`s antioxidant capacity and its ability to conjugate with glutathione.93

Curcumin III was more active than curcumin I and II as a cytotoxic agent in vitro and in the inhibition of Ehrlich ascites tumour in mice by intraperitoneal infection.94 Curcumin inhibited the proliferation and cell cycle progression of human umbilical vein endothelial cells. It demonstrated a unique mode of action by effectively blocking the cell cycle progression during the S-phase by inhibiting the activity of thymidine kinase enzyme.95 Curcumin therefore is a potential angiogenesis inhibitor in vitro.

Other activity

Curcumin inhibited human immunodeficiency virus type-1 integrase in vitro96 and is a modest inhibitor of the HIV-1 and HIV-2 proteases.97

Turmeric (4 g/kg) and curcumin (0.4 g/kg) induced significant increases in hepatic levels of glutathione-S-transferase and acid soluble sulphydryl after 14 or 21 days` treatment in lactating mice and translactationally exposed mouse pups. Cytochrome B-5 and cytochrome P-450 levels were significantly elevated in the mice and their pups.98

Curcumin inhibited lipopolysaccharide-induced production of tumour necrosis factor (TNF) and inter-leukin-1-beta by a human monocytic macrophage cell line. It also inhibited lipopolysaccharide-induced activation of nuclear factor kappa B and reduced the biological activity of TNF in a fibroblast lytic assay.99 Curcuminoids (I-IV) were ineffective as nematocidal agents when applied independently but the activity increased markedly when mixed, suggesting a synergistic action.100

In human peripheral blood mononuclear cells, cur-cumin dose dependently inhibited the responses to phytohaemagglutinin and mixed lymphocyte reaction. It dose dependently inhibited the proliferation of rabbit vascular smooth muscle cells stimulated by foetal calf serum. Curcumin had a greater inhibitory effect on platelet-derived growth factor-stimulated proliferation than on serum-stimulated proliferation. The characteristics of the curcumin molecule itself were necessary for the activity. Curcumin may therefore be beneficial in the prevention of the pathological changes of atherosclerosis and restenosis.101

Pharmacokinetics

The uptake, distribution and excretion of curcumin was studied in rats.102 When administered orally in a single dose, 65-85% of curcumin passes through the gastrointestinal tract unchanged and was found in the faeces, while traces appeared in the urine. Only a small amount of curcumin was found in the bile, liver, kidneys and body fat. After intravenous injection curcumin is actively transported into bile but the majority is rapidly metabolized by the liver.

The poor bioavailability of curcumin was confirmed in a subsequent study on rats, which found that 38% of the administered 400 mg dose remained unchanged in the digestive tract.103 Only traces were found in body tissues and no curcumin was detected in urine. A subsequent in vitro study suggested that curcumin undergoes transformation to a less polar, colourless compound during absorption from the intestine.104 This was confirmed using radiolabelled curcumin.105 While significant levels of radioactivity were absorbed, only traces of curcumin could be measured in body tissues.

When curcumin was given alone in a dose of 2 g/kg to rats, only moderate serum concentrations were achieved over a 4-hour period.106 Concomitant administration of piperine at 20 mg/kg increased bioavailability by 154%. Administration of 20 mg of piperine to 10 healthy volunteers increased the relative bioavailability of curcumin by 20 times. However, the absolute bioavailability of curcumin under these conditions was still less than 10% and the elimination half-life was relatively rapid at 0.41 ± 0.17 h.

Toxicology

Acute and subacute toxicity

The oral LD50 in rats of the petroleum ether extract of turmeric was 12.2 g/kg.25 No toxic effects were observed when this extract was fed to rats at levels of 1 and 2 g/kg for 4 weeks. Rats, guinea pigs and monkeys given 2.5 g/kg of turmeric or 300 mg/kg of the ethanolic extract showed no signs of toxicity and no change in organ weights.120

No toxic effects were observed when oral doses of curcumin were given to mice up to 2 g / kg13 and rats up to 5 g/kg.102 Sodium curcuminate was not toxic to rats at 3 g/kg in an acute study and at 50 mg/kg/day in a study of 6 weeks` duration.15

The acute and chronic toxicity of a 20:1 turmeric ethanolic extract was studied in mice. Acute dosages of extract, given over 24 hours, were 0.5, 1.0 and 3 g/kg body weight and the chronic dosage, given over 90 days, was 100 mg/kg per day. There was no significant body weight gain after chronic treatment. Significant gains in heart and lung weights after chronic treatment were observed. There was a significant fall in the white blood cell and red blood cell levels and there were gains in weight of sexual organs and increased sperm motility but no spermatotoxic effects. No significant mortality or toxic effects were observed after acute doses.121

Chronic toxicity and mutagenicity

Turmeric oleoresin (which consists mainly of curcuminoids and essential oil) was fed for 102-109 days to pigs at doses of 60, 296 and 1551 mg/kg. Thyroid enlargement, pericholangitis and epithelial changes in the kidney and bladder were observed in the two higher dose groups. Liver and thyroid weight were increased at all dose levels. The highest dosage group also showed a reduction in weight gain.122 Turmeric extract and turmeric powder caused hepatotoxicity when fed to mice for 14 days or longer.123,124 The mouse is probably a susceptible species for turmeric-induced toxicity.

Turmeric extract in direct contact with mammalian cells in vitro caused cytotoxic effects such as chromosomal separation and breakage and mitotic arrest.92 Turmeric also caused chromosomal breakage in onion root tip cells.125 However, turmeric, turmeric oleoresin and curcumin were not mutagenic in vitro in the Ames test69,126 or in vivo.127,128 Absence of mutagenicity in vitro was also reported for turmeric extract following activation with caecal microorganisms.129 Curcumin and the synthetic dye tartrazine were compared for their chromosome-damaging effects on bone marrow cells of mice in vitro. Tartrazine was found to be more clastogenic than curcumin.130

Turmeric ethanolic extract was administered to mice (4 mg/kg per day) in their food for 4 weeks while a control group was fed a standard diet. Blood and liver samples taken after treatment indicated that turmeric did not result in any toxic effects on the physiological, behavioural and biochemical parameters measured.46 Turmeric extracts show antifertility effects at high doses in rats and rabbits.131

Clinical data

Clinical trials

Antiinflammatory activity

In a short-term, double-blind trial on rheumatoid arthritis patients, curcumin (120 mg per day) was compared with phenylbutazone. A significant symptom improvement occurred with curcumin but phenylbutazone gave greater improvement, probably because it also has analgesic activity.107 When postoperative inflammation was used as a model for evaluating anti-inflammatory activity, curcumin (1200 mg per day) was found to have greater activity than phenylbutazone or placebo in a double-blind clinical trial.108 In both the above trials, use of curcumin was devoid of significant side effects.

In a double-blind, placebo-controlled crossover trial, 42 osteoarthritis patients received either a herb/mineral preparation or placebo for 3 months. After a 15-day wash-out period the patients were transferred to the other treatment for a further 3-month period. The preparation consisted of turmeric, Withania somnifera, Boswellia serrata and a zinc complex. Treatment with the herb/mineral preparation produced a significant drop in severity of pain (p < 0.001) and disability score (p < 0.05). Radiological assessment did not show any significant changes in either group. Side effects did not necessitate withdrawal of treatment.109

Hypolipidaemic activity

An uncontrolled clinical trial on 16 patients in China found that 12 weeks of turmeric extract (equivalent to about 50 g/ day of turmeric) lowered plasma cholesterol levels by 49 mg/dl (1.3 mmol/l) and triglycerides by 62 mg/dl.4 The therapeutic effect was at least equal to clofibrate. Another study on 90 subjects found cholesterol and triglyceride levels were reduced by turmeric in almost all cases.4 It was found in both studies that use of turmeric somewhat ameliorated the symptoms of angina pectoris.

Anticancer or preventative activity

In an open study, 58 patients with submucous fibrosis received one of the following treatments each day for 3 months: turmeric essential oil (600 mg) mixed with turmeric extract (3 g), turmeric oleoresin (600 mg) mixed with turmeric extract (3 g) or turmeric extract (3 g). Thirty-nine patients completed the treatment and results were compared to 32 healthy subjects who served as a control. All three treatments normalized the number of micronucleated cells both in exfoliated oral mucosal cells and in circulating lymphocytes. Turmeric oleoresin was more effective in reducing the number of micronuclei in oral mucosal cells (p < 0.001) than the other two treatments. The decrease in micronuclei in circulating lymphocytes was comparable in all three groups.110

Turmeric given in doses of 1.5 g/day for 30 days to 16 chronic smokers significantly reduced the urinary excretion of mutagens in an uncontrolled trial. In six non-smokers who served as controls, there was no change in the urinary excretion of mutagens after 30 days. Turmeric had no significant effect on serum aspartate aminotransferase and alanine aminotransferase, blood glucose, creatinine and lipid profile.111

In an uncontrolled trial, a 50% ethanol extract of turmeric and an ointment containing curcumin produced symptomatic relief in patients with external cancerous lesions which had failed to respond to conventional treatments.112 There was a reduction in the odour of the lesions in 90% of cases and also reduction in itching and exudation. In a small number of patients (10%) the thickness of the lesion was reduced.

Digestive tract

The safety and efficacy of turmeric for the treatment of undiagnosed dyspepsia were tested in a three-way, randomized, double-blind, placebo-controlled trial over 7 days.113 Forty-one patients were in the placebo group, 36 received a herbal formula for flatulence and 39 received 2 g of turmeric powder per day. An 87% favourable outcome was recorded for the turmeric group which was significantly different to the 53% improvement for the placebo group (p=0.003). Mild side effects were observed with similar frequency in all three groups.

The effect of turmeric (1000 mg/day) was com-pared with an antacid formulation in 50 patients over 6 weeks in an open study of the treatment of gastric ulcer.114 The antacid formula was significantly superior to turmeric in inducing ulcer healing (p < 0.05). In a joint Vietnam-Sweden prospective, double-blind, two-centre study, turmeric in a dosage of 6 g daily, as suggested in the Vietnamese Pharmacopoeia, was compared with placebo in 118 patients suffering from duodenal ulcer.115 Follow-up endoscopy and/or radiography were performed after 28 ± 4 days and 56 ± 4 days. Turmeric was not superior to placebo in healing duodenal ulcer after either 4 or 8 weeks of treatment. After 8 weeks the ulcer-healing rate of turmeric was 27% while placebo had healed 29%. Both treatments were well tolerated.

HIV/AIDS

Following pharmacological research which suggested that curcumin might weakly inhibit the LTR (long terminal repeat) of HIV-1, a clinical study was conducted. Eighteen HIV-positive patients took an average of 2 g curcumin a day for an average of 127 days.116 There was a significant increase in CD4 (p=0.029) and CD8 (p=0.009) lymphocyte counts. A follow-up phase I/II open study using doses of 2.7 g and 4.8 g of curcumin per day failed to show any benefit on viral loads or CD4 count in HIV-positive individuals.117 It was suggested that the poor bioavailability of curcumin may have been a factor behind this negative result.118

Other conditions

A paste consisting of turmeric and neem (Azadirachta indica) used in the treatment of scabies in 814 patients resulted in cure in 97% within 3-15 days of treatment. No toxic or adverse reactions were observed.119

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