13.1. INTRODUCTION

Natural plant products have been used throughout human history for various purposes. Having co-evolved with animal life, many of the plants from which these natural products are derived are billions of years old. Tens of thousands of these products are produced as secondary metabolites by higher plants as a natural defense mechanism against disease and infection. Many of these natural products have pharmacological or biological activity that can be exploited in pharmaceutical drug discovery and drug design. Medicines derived from plants have played a pivotal role in the health care of many cultures, both ancient and modern (Newman, Cragg, and Sander 2003; Butler 2004; Balunas and Kinghorn 2005; Gurib-Fakim 2006; Newman and Cragg 2007). The Indian system of holistic medicine known as “Ayurveda” uses mainly plant-based drugs or formulations to treat various ailments, including cancer. Of the at least 877 small-molecule drugs introduced worldwide between 1981 and 2002, the origins of most (61%) can be traced to natural products (Newman and Cragg 2007). Although many synthetic drugs are produced through combinatorial chemistry, plant-based drugs are more suitable, at least in biochemical terms, for human use. Nonetheless, modern medicine has neither held in very high esteem nor encouraged the medicinal use of natural products.

Turmeric is a plant that has a very long history of medicinal use, dating back nearly 4000 years. In Southeast Asia, turmeric is used not only as a principal spice but also as a component in religious ceremonies. Because of its brilliant yellow color, turmeric is also known as “Indian saffron.” Modern medicine has begun to recognize its importance, as indicated by the over 3000 publications dealing with turmeric that came out within the last 25 years. This review first discusses in vitro studies with turmeric, followed by animal studies, and finally studies carried out on humans; the safety and efficacy of turmeric are further addressed.

13.2. ORIGIN, NOMENCLATURE, HISTORY, CULTIVATION, AND PROCESSING OF TURMERIC

The use of turmeric dates back nearly 4000 years to the Vedic culture in India, where it was used as a culinary spice and had some religious significance. It probably reached China by 700 ad, East Africa by 800 ad, West Africa by 1200 ad, and Jamaica in the eighteenth century. In 1280, Marco Polo described this spice, marveling at a vegetable that exhibited qualities so similar to that of saffron. According to Sanskrit medical treatises and Ayurvedic and Unani systems, turmeric has a long history of medicinal use in South Asia. Susruta’s Ayurvedic Compendium, dating back to 250 BC, recommends an ointment containing turmeric to relieve the effects of poisoned food.

Today, turmeric is widely cultivated in the tropics and goes by different names in different cultures and countries (Table 13.1). In North India, turmeric is commonly called “haldi,” a word derived from the Sanskrit word haridra, and in the south it is called “manjal,” a word that is frequently used in ancient Tamil literature. The name turmeric derives from the Latin word terra merita (meritorious earth), referring to the color of ground turmeric, which resembles a mineral pigment. It is known as terre merite in French and simply as “yellow root” in many languages. In many cultures, its name is based on the Latin word curcuma. In Sanskrit, turmeric has at least 53 different names, including anestha (not offered for sacrifice or homa), bhadra (auspicious or lucky), bahula (plenty), dhirgharaja (long in appearance), gandhaplashika (which produces good smell), gauri (to make fair), gharshani (to rub), haldi (that draws attention to its bright color), haridra (dear to hari, Lord Krishna), harita (greenish), hemaragi (exhibits golden color), hemaragini (gives the golden color), hridayavilasini (gives delight to heart, charming), jayanti (one that wins over diseases), jawarantika (which cures fevers), kanchani (exhibits golden color), kaveri (harlot), krimighni or kashpa (killer of worms), kshamata (capability), laxmi (prosperity), mangalprada (who bestows auspiciousness), mangalya (auspicious), mehagni (killer of fat), nisha (night), nishakhya (known as night), nishawa (clears darkness and imparts color), patwaluka (perfumed powder), pavitra (holy), pinga (reddish-brown), pinja (yellow-red powder), pita (yellow), pitika (which gives yellow color), rabhangavasa (which dissolves fat), ranjani (which gives color), ratrimanika (as beautiful as moonlight), shifa (fibrous root), shobhna (brilliant color), shiva (gracious), shyama (dark colored), soubhagaya (lucky), survana (golden color), survanavara (which exhibits golden color), tamasini (beautiful as night), umavara (Parvati, wife of Lord Shiva), vairagi (who remains free from desires), varavarnini (which gives fair complexion), varna datri (enhancer of body complexion), varnini (which gives color), vishagni (killer of poison), yamini (night), yoshitapriya (beloved of wife), and yuvati (young girl).

TABLE 13.1

Various Names of Turmeric/Curcumin in Different Languages.

Turmeric is a product of Curcuma longa, a rhizomatous herbaceous perennial plant belonging to the ginger family Zingiberaceae, which is native to tropical South Asia. As many as 133 species of Curcuma have been identified worldwide (Table 13.2). Most of them have common local names and are used for various medicinal formulations. Some specific turmeric species are shown in Figure 13.1. The turmeric plant needs temperatures between 20°C and 30°C and a considerable amount of annual rainfall to thrive. Individual plants grow to a height of 1 m, and have long, oblong leaves. Plants are gathered annually for their rhizomes, and are reseeded from some of those rhizomes in the following season. The rhizome, from which the turmeric is derived, is tuberous, with a rough and segmented skin. The rhizomes mature beneath the foliage in the ground. They are yellowish brown with a dull orange interior. The main rhizome is pointed or tapered at the distal end and measures 2.5–7.0 cm (1–3 inches) in length and 2.5 cm (1 inch) in diameter, with smaller tubers branching off. When the turmeric rhizome is dried, it can be ground to a yellow powder with a bitter, slightly acrid, yet sweet, taste.

TABLE 13.2

List of Curcuma Species.

FIGURE 13.1

(See color insert.) Different species of Curcuma that are used traditionally as a spice or as medicine.

India produces nearly all of the world’s turmeric crop and consumes 80% of it. With its inherent qualities and high content of the important bioactive compound curcumin, Indian turmeric is considered to be the best in the world. Erode, a city in the South Indian state of Tamil Nadu, is the world’s largest producer of and the most important trading center for turmeric. It is also known as “Yellow City,” “Turmeric City,” or “Textile City.” Sangli, a city of Maharashtra, is second only to Erode in size and importance as a production and trading site for turmeric.

Before turmeric can be used, the turmeric rhizomes must be processed. Rhizomes are boiled or steamed to remove the raw odor, gelatinize the starch, and produce a more uniformly colored product. In the traditional Indian process, rhizomes were placed in pans or earthenware filled with water and then covered with leaves and a layer of cow dung. The ammonia in the cow dung reacted with the turmeric to give the final product. For hygienic reasons, this method has been discouraged. In present-day processing, rhizomes are placed in shallow pans in large iron vats containing 0.05–0.1% alkaline water (e.g., solution of sodium bicarbonate). The rhizomes are then boiled for between 40–45 minutes (in India) or 6 hours (in Hazare, Pakistan), depending on the variety. The rhizomes are removed from the water and dried in the sun immediately to prevent overcooking. The final moisture content should be between 8% and 10% (wet basis). When finger tapping of the rhizome produces a metallic sound, it is sufficiently dry. The dried rhizomes are polished to remove the rough surface. Sometimes, lead chromate is used to produce a better finish, but for obvious reasons this practice should be actively discouraged. The powder maintains its coloring properties indefinitely, although the flavor may diminish over time. Protecting the turmeric powder from sunlight retards the rate of deterioration.

13.3. COMPOSITION OF TURMERIC

More than 100 components have been isolated from turmeric. The main component of the root is a volatile oil, containing turmerone, and there are other coloring agents called curcuminoids in turmeric. Curcuminoids consist of curcumin demethoxycurcumin, 5’-methoxycurcumin, and dihydrocurcumin, which are found to be natural antioxidants (Ruby et al. 1995; Selvam et al. 1995). In a standard form, turmeric contains moisture (>9%), curcumin (5–6.6%), extraneous matter (<0.5% by weight), mould (<3%), and volatile oils (<3.5%). Volatile oils include d-α-phellandrene, d-sabinene, cinol, borneol, zingiberene, and sesquiterpenes (Ohshiro, Kuroyanag, and Keno 1990). There are a variety of sesquiterpenes, like germacrone; termerone; ar-(+)-, α-, and β-termerones; β-bisabolene; α-curcumene; zingiberene; β-sesquiphellanderene; bisacurone; curcumenone; dehydrocurdione; procurcumadiol; bis-acumol; curcumenol; isoprocurcumenol; epiprocurcumenol; procurcumenol; zedoaronediol; and curlone, many of which are specific for a species. The components responsible for the aroma of turmeric are turmerone, arturmerone, and zingiberene. The rhizomes are also reported to contain four new polysaccharides-ukonans along with stigmasterole, β-sitosterole, cholesterol, and 2-hydroxymethyl anthraquinone (Kapoor 1990; Kirtikar and Basu 1993). Nutritional analysis showed that 100 g of turmeric contains 390 kcal, 10 g total fat, 3 g saturated fat, 0 mg cholesterol, 0.2 g calcium, 0.26 g phosphorous, 10 mg sodium, 2500 mg potassium, 47.5 mg iron, 0.9 mg thiamine, 0.19 mg riboflavin, 4.8 mg niacin, 50 mg ascorbic acid, 69.9 g total carbohydrates, 21 g dietary fiber, 3 g sugars, and 8 g protein (Balakrishnan 2007). Turmeric is also a good source of the ω-3 fatty acid and α-linolenic acid (2.5%; Goud, Polasa, and Krishnaswamy 1993).

13.4. CONSUMPTION AND IMPORTANCE OF TURMERIC

Turmeric has been put to use as a foodstuff, cosmetic, and medicine. It is widely used as a spice in South Asian and Middle Eastern cooking. It lends curry its distinctive yellow color and flavor. It is used as a coloring agent in cheese, butter, and other foods (Govindarajan 1980; Ammon and Wahl 1991). As a result of Indian influence, turmeric has made its way into Ethiopian cuisine. In South Africa, turmeric is traditionally used to give boiled white rice a golden color. Turmeric is also used in manufactured food products such as canned beverages, dairy products, baked products, ice cream, yellow cakes, yogurt, orange juice, biscuits, popcorn, sweets, cake icings, cereals, sauces, and gelatins. It is a significant ingredient in most commercial curry powders. Turmeric has numerous uses in Asian cuisine. It is used in savory and sweet dishes, and is widely used in Eastern specialties such as fresh turmeric pickle. The reported consumption of turmeric in Asian countries in humans is in the range of 200–1000 mg/day (Thimmayamma, Rau, and Radhaiah 1983; Polasa et al. 1991) or 160–440 g/person/year (Krishnaswamy 1996). Intake in urban areas is lower (200 mg/day) than in rural areas (600 mg/day/person; Thimmayamma, Rau, and Radhaiah 1983).

According to some estimates, as much as USD $10 billion is spent every year on alternative therapies. Over USDA $650 million is spent on botanical supplements that are used for chronic inflammatory diseases such as chronic obstructive airways disease (COPD), asthma, and rheumatoid arthritis. Botanical supplements have been used for centuries in traditional medicine, including Ayurveda (science of long life), Chinese medicine, Kampo (Japanese medicine), and Egyptian medicine. Several of the medicines that are traditionally used exhibit anti-inflammatory activities (Garodia et al. 2007; Aggarwal et al. 2006). Turmeric is one such herb.

Turmeric is used as an herbal medicine for rheumatoid arthritis, chronic anterior uveitis, conjunctivitis, skin cancer, small pox, chicken pox, wound healing, urinary tract infections, and liver ailments (Dixit, Jain, and Joshi 1988). It is also used for digestive disorders; to reduce flatus, jaundice, menstrual difficulties, and colic; for abdominal pain and distension (Bundy et al. 2004); and for dyspeptic conditions including loss of appetite, postprandial feelings of fullness, and liver and gallbladder complaints. It has anti-inflammatory, choleretic, antimicrobial, and carminative actions (Mills and Bone 2000). The main clinical targets of turmeric are the digestive organs: in the intestine, for treatment of diseases such as familial adenomatous polyposis (Cruz-Correa et al. 2006); in the bowels, for treatment of inflammatory bowel disease (Hanai and Sugimoto 2009); and in the colon, for treatment of colon cancer (Naganuma et al. 2006). For arthritis, dosages of 8–60 g of fresh turmeric root three times daily have been recommended (Fetrow and Avila 1999). For dyspepsia, 1.3–3.0 g of turmeric root is recommended. No known interaction of drugs with turmeric has been reported by the monographs of the German regulatory authority, Commission E (Blumenthal, Goldberg, and Brinckmann 2000).

13.5. TURMERIC AS A TRADITIONAL MEDICINE

In folk medicine, turmeric has been used in therapeutic preparations over the centuries in different parts of the world. In Ayurvedic practices, turmeric is thought to have many medicinal properties including strengthening the overall energy of the body, relieving gas, dispelling worms, improving digestion, regulating menstruation, dissolving gallstones, and relieving arthritis. Many South Asian countries use it as an antiseptic for cuts, burns, and bruises, and as an antibacterial agent. In Pakistan, it is used as an anti-inflammatory agent, and as a remedy for gastrointestinal discomfort associated with irritable bowel syndrome and other digestive disorders. In Pakistan and Afghanistan, turmeric is used to cleanse wounds and stimulate their recovery by applying it on a piece of burnt cloth that is placed over a wound. Indians use turmeric, in addition to its Ayurvedic applications, to purify blood and remedy skin conditions. Turmeric paste is used by women in some parts of India to remove superfluous hair. Turmeric paste is applied to the skin of the bride and groom before marriage in some parts of India, Bangladesh, and Pakistan, where it is believed to make the skin glow and keep harmful bacteria away from the body. Turmeric is currently used in the formulation of several sunscreens. Several multinational companies are involved in making face creams based on turmeric.

In Ayurvedic medicine, turmeric is a well-documented treatment for various respiratory conditions (e.g., asthma, bronchial hyperactivity, and allergy), as well as for liver disorders, anorexia, rheumatism, diabetic wounds, runny nose, cough, and sinusitis (Araujo and Leon 2001). In traditional Chinese medicine, it is used to treat diseases associated with abdominal pain (Aggarwal, Ichikawa, and Garodia 2004). From ancient times, as prescribed by Ayurveda, turmeric has been used to treat sprains and swelling (Araujo and Leon 2001). In both Ayurvedic and traditional Chinese medicine, turmeric is considered a bitter digestive and a carminative. Unani practitioners also use turmeric to expel phlegm or kapha, as well as to open blood vessels in order to improve blood circulation. It can be incorporated into foods, including rice and bean dishes, to improve digestion and reduce gas and bloating. It is a cholagogue, stimulating bile production in the liver and encouraging excretion of bile via the gallbladder, which improves the body’s ability to digest fats. Sometimes, turmeric mixed with milk or water is taken to treat intestinal disorders as well as colds and sore throats.

13.6. FROM TRADITIONAL MEDICINE TO MODERN MEDICINE

Although modern medicine has been routinely used in treatment of various diseases, it is less than 100 years old. Traditional medicine, in comparison, has served mankind for thousands of years, is quite safe and effective. The mechanism or the scientific basis of traditional medicine, however, is less well understood.

13.6.1. In Vitro Studies with Turmeric

Throughout the Orient, turmeric is traditionally used for both prevention and therapy of diseases. Modern in vitro studies reveal that turmeric is a potent antioxidant, anti-inflammatory, antimutagenic, antimicrobial, and anticancer agent (Table 13.3). Turmeric, used in cooking and in home remedies, has significant antioxidant abilities at different levels of action. Studies indicate that sufficient levels of turmeric may be consumed from curries in vivo to ensure adequate antioxidant protection. (Tilak et al. 2004). As an antioxidant, turmeric extracts can scavenge free radicals, increase antioxidant enzymes, and inhibit lipid peroxidation. Turmeric (100 μg/mL) inhibits lipid peroxidation in renal cells against hydrogen peroxide-induced injury when incubated with cells for 3 hours (Cohly et al. 1998). Using Salmonella typhimurium strains TA 100 and TA 1535, a mutagenicity study showed that turmeric inhibits the mutagenicity produced by direct-acting mutagens such as N-methyl N’-nitro-N-nitrosoguanidine and sodium azide. Turmeric extracts were found to inhibit microsomal activation-dependent mutagenicity of 2-acetamidofluorene (Soudamini et al. 1995).

TABLE 13.3

In Vitro Effects of Turmeric against Various Diseases/Disorders.

Numerous lines of evidence suggest that turmeric exhibits anti-inflammatory activity. In one study, crude organic extracts of turmeric were found to inhibit lipopolysaccharide (LPS)-induced production of tumor necrosis factor (TNF)-α (median inhibitory concentration [IC₅₀] value = 15.2 μg/mL) and prostaglandin E2 (PGE2; IC₅₀ value = 0.92 μg/mL) from HL-60 cells. A combination of several fractions that contained the turmeric oils was more effective than curcuminoids in inhibiting PGE2 production (Lantz et al. 2005). A hydroethanolic extract of turmeric was recently found to inhibit activation of human dendritic cells in response to inflammatory cytokines (Krasovsky et al. 2009).

Besides these properties, turmeric has strong antimicrobial properties. The growth of histamine-producing bacteria (Vibrio parahaemolyticus, Bacillus cereus, Pseudomonas aeruginosa, and Proteus mirabilis) was inhibited by garlic and turmeric extracts at a 5% concentration (Paramasivam, Thangaradjou, and Kannan 2007). Turmeric was also found to inhibit histamine production in Morganella morganii (potent histamine-producing bacteria). However, inhibition of histamine production and histidine decarboxylase activity of turmeric is less than that of clove and cinnamon (Shakila, Vasundhara, and Rao 1996). Turmeric extract was found to inhibit growth of the foodborne pathogen V. parahaemolyticus with good sensitivity (Yano, Satomi, and Oikawa 2006). A methanolic extract of turmeric inhibited the growth of different strains of Helicobacter pylori with a minimum inhibitory concentration range of 6.25–50.0 μg/mL (Mahady et al. 2002). Among the various plant extracts that killed H. pylori, such as cumin, ginger, chili, borage, black caraway, oregano, and licorice, turmeric was found to be the most efficient (O’Mahony et al. 2005).

Ethanolic extracts of C. longa have good antifungal activity against Trichophyton longifusus (Khattak et al. 2005). Tests using the agar disc diffusion method for detecting antifungal activity showed that a crude ethanolic extract of turmeric killed all 29 tested clinical strains of dermatophytes. This extract exhibited an inhibition zone range of 6.1–26.0 mm (Wuthi-udomlert et al. 2000).

The anticancer activities of turmeric include inhibiting cell proliferation and inducing apoptosis of cancer cells. Ar-turmerone, which is isolated from turmeric, induced apoptosis in human leukemia Molt 4B and HL-60 cells by fragmenting DNA to oligonucleosome-sized fragments, a known step in the process of apoptosis (Aratanechemuge et al. 2002). Moreover, the nucleosomal DNA fragmentation induced by ar-turmerone was associated with induction of Bax and p53 proteins, rather than B cell lymphoma 2 (Bcl-2) and p21, and activation of mitochondrial cytochrome c and caspase-3 (Lee 2009). This study showed that turmeric extract repressed the production and secretion of hepatitis B surface antigen from HepG 2.2.15 cells, an activity that is mediated through the enhancement of cellular accumulation of p53 protein by transactivating the transcription of the p53 gene as well as increasing the stability of the p53 protein (Kim et al. 2009).

13.6.2. In Vivo Studies with Turmeric

Both the preventive and therapeutic effects of turmeric have been examined in animal models (Table 13.4). These studies report that this yellow spice exhibits anticancer (Azuine and Bhide 1994; Deshpande, Ingle, and Maru 1997; Garg, Ingle, and Maru 2008), hepatoprotective (Miyakoshi et al. 2004), cardioprotective (Mohanty, Arya, and Gupta 2006), hypoglycemic (Kuroda et al. 2005; Honda et al. 2006), and antiarthritic properties (Funk et al. 2006).

TABLE 13.4

In Vivo Effect of Turmeric against Development of Various Diseases/Disorders.

In various models, turmeric has been reported to exhibit activity against the development of skin cancer (Villaseñlor, Simon, and Villanueva 2002), breast cancer (Deshpande, Ingle, and Maru 1998a), oral cancer (Azuine and Bhide 1992a), and stomach cancer (Azuine and Bhide 1992b). It prevents carcinogenesis at various steps, including inhibiting mutation (Polasa et al. 1991), detoxifying carcinogens (Thapliyal, Deshpande, and Maru 2001), decreasing cell proliferation, and inducing apoptosis of tumor cells (Garg, Ingle, and Maru 2008). Turmeric extract prevents animal tumors induced by Dalton’s lymphoma (Kuttan et al. 1985). In this study, mice were injected with Dalton’s lymphoma cells intraperitoneally and treated with turmeric extract (10–40 mg/animal) for 10 days. After 30 days, the authors found up to 80% decrease in tumor formation in comparison with nontreated mice (Figure 13.2a). They also observed that up to 75% of animals survived after 30 days and 50% after 60 days of treatment (Figure 13.2b). In a 7,12-dimethylbenz(a)anthracene (DMBA)-induced hamster buccal pouch model of carcinogenesis, dietary turmeric (1%) decreased tumor burden and multiplicity and enhanced the latency period in parallel. The mechanisms of anticarcinogenesis were mediated through inhibition of DMBA-induced expression of the ras oncogene product, induction of p21 and its downstream targets, mitogen-activated protein kinases, and reduction of proliferating cell nuclear antigen and Bcl-2 expression. Turmeric also enhanced apoptosis (increased expression of Bax, caspase-3, and apoptotic index), decreased inflammation (levels of cyclooxygenase [COX]-2, the downstream target of activator protein-1/nuclear factor KB [NF-KB], and PGE2), and induced aberrant expression of known differentiation markers, that is, cytokeratins (Garg, Ingle, and Maru 2008).

FIGURE 13.2

Inhibition of tumor growth in mice by turmeric extracts in a dose-dependent manner. Mice were injected with Dalton’s lymphoma cells (1 million) intraperitoneally. After randomization, turmeric was given to the mice (n = 8) at indicated concentration (more...)

Topical application of turmeric was found to decrease multiplicity and onset of skin tumors (Villaseñor, Simon, and Villanueva 2002). Dietary administration of 1% turmeric per 0.05% ethanolic turmeric extract was found to inhibit DMBA-induced mammary tumorigenesis in female Sprague–Dawley rats (Deshpande, Ingle, and Maru 1998a). Dietary turmeric inhibited ethyl(acetoxymethyl) nitrosamine-induced oral carcinogenesis in Syrian hamsters. However, the inhibitory effect of a combination of turmeric and betel leaf extract was found to be higher than that of the individual constituents (Azuine and Bhide 1992a). Administration of turmeric extract at a dose of 3 mg/animal 18 hours prior to intraperitoneal (i.p.) injection of benzo[a]pyrene (BaP; 250 mg/kg) significantly inhibited bone marrow micronuclei formation in female Swiss mice. Moreover, the incidence and multiplicity of BaP-induced forestomach tumors in female Swiss mice were significantly inhibited by turmeric extract (Azuine, Kayal, and Bhide 1992). Chandra Mohan, Abraham, and Nagini (2004) also showed that pretreatment with turmeric alone and in combination with tomato and garlic extract significantly lowered the frequencies of DMBA-induced bone marrow micronuclei, as well as the extent of lipid peroxidation. They revealed that these changes may be mediated by the antioxidant-enhancing effects of the dietary agents. Combined treatment of urethane, a well-known mutagen, and turmeric displayed an inhibition of the genotoxic effect of urethane by turmeric (el Hamss et al. 1999). Decrease in tumorigenesis caused by turmeric is also associated with inhibition of DNA adduct formation. Turmeric inhibited the levels of BaP-induced DNA adducts in the livers of rats. Inclusion of turmeric at 0.1%, 0.5%, and 3.0% in the diet for 4 weeks significantly decreased the level of BaP–DNA adducts, including the major adduct dG-N2-BaP, formed within 24 hours in response to a single i.p. BaP injection (Mukundan et al. 1993). Irrespective of whether turmeric was included in the diet or applied locally, it significantly decreased DMBA-induced DNA adducts at the target site and consequently lowered the number of tumors and tumor burden in the studied animals (Krishnaswamy et al. 1998). Turmeric contains several substances capable of inhibiting chemical carcinogenesis. It enhanced the xenobiotic-metabolizing enzymes in the hepatic tissue of rats fed with 0.5–1.0% turmeric in the diet. Detoxifying enzymes such as uridine diphosphate (UDP), glucuronyl transferase, and glutathione-S-transferase significantly increased in turmeric-fed mice as compared with control animals (Goud, Polasa, and Krishnaswamy 1993).

Ethanolic turmeric extract was found to have opposing actions on murine lymphocytes and on Ehlrich ascitic carcinoma cells. Turmeric enhances lymphocyte viability and blastogenesis, but induces formation of cytoplasmic blebs and plasma membrane disintegration of tumor cells. Thus, it is suggested that turmeric is a conducive agent for lymphocytes and inhibitory as well as apoptosisinducing for tumor cells (Chakravarty and Yasmin 2005). A comparative study of edible plants like C. longa and F. caraica, and herbaceous plants like Gossypium barbadense and Ricinus communis extracts for their antitumor activities showed that the edible plant extracts exhibited higher antitumorigenic activities. Thus, edible plants that show in vivo antitumor activities may be recommended as safe sources of antitumor compounds (Amara, El-Masry, and Bogdady 2008).

Turmeric showed antioxidant potential by lowering oxidative stress in animals. A study showed that a diet containing 0.1% turmeric fed for 3 weeks to retinol-deficient rats lowered lipid peroxidation rates by 22.6% in liver, 24.1% in kidney, 18.0% in spleen, and 31.4% in brain (Kaul and Krishnakantha 1997). A study conducted on mice showed that turmeric extract inhibited membrane phospholipid peroxidation and increased liver lipid metabolism, which indicates turmeric extract has the ability to prevent the deposition of triacylglycerols in the liver. Dietary supplementation for one week (1% w/w of diet) with a turmeric extract showed lower phospholipids hydroperoxide level in mice red blood cells (RBC). The liver lipid peroxidizability induced with Fe²⁺/ascorbic acid was effectively suppressed by dietary supplementation with turmeric (Asai, Nakagawa, and Miyazawa 1999). Oral administration of a nutritional dose of turmeric extract decreased susceptibility to oxidation of erythrocyte and liver microsome membranes in vitro. When turmeric hydroalcoholic extract (1.66 mg/kg of body weight) was given to rabbits fed a high-fat diet, oxidation of erythrocyte membranes was found to be significantly lower than that in membranes of control animals. Levels of hydroperoxides and thiobarbituric acid-reactive substances in liver microsomes were also low (Mesa et al. 2003). Turmeric also seems beneficial in preventing diabetes-induced oxidative stress. In diabetic rats, an AIN93 diet containing 0.5% turmeric was found to control oxidative stress by inhibiting increases in thiobarbituric acid-reactive substances and protein carbonyls and reversing altered antioxidant enzyme activities without altering the hyperglycemic state (Arun and Nalini 2002; Suryanarayana et al. 2007). This diet also inhibited expression of vascular endothelial growth factor in diabetic rats (Mrudula et al. 2007). Further, it suppressed increase in blood glucose level in type 2 diabetic KK-Ay mice. A dose of 0.2 or 1.0 g of ethanol extract, 0.5 g of hexane extract, and 0.5 g of hexane-extraction residue per 100 g of diet in the mice feed suppressed significant increase in blood glucose levels. The ethanol extract of turmeric also stimulated human adipocyte differentiation, and it showed human peroxisome proliferator-activated receptor-gamma (PPAR-γ) ligand-binding activity (Nishiyama et al. 2005). Further, turmeric appeared to minimize osmotic stress. Most importantly, aggregation and insolubilization of lens proteins due to hyperglycemia was prevented by turmeric, indicating that it prevents or delays the development of cataracts (Suryanarayana et al. 2005).

Turmeric has been reported to be hepatoprotective. Diets containing turmeric extract suppressed increases in lactate dehydrogenase (LDH), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) levels caused by D-galactosamine-induced liver injury in rats (Miyakoshi et al. 2004). A 5% turmeric extract decreased carbon tetrachloride–induced increases in serum levels of bilirubin, cholesterol, AST, ALT, and alkaline phosphatase (ALP) in mice (Deshpande et al. 1998b). In female Wistar rats fed a diet containing 0%, 0.2%, 1.0%, or 5.0% turmeric, nitrosodiethylamineinduced hepatocarcinogenesis was inhibited. This effect was detected by measuring the numbers of γ-glutamyl transpeptidase–positive foci, a marker of hepatocarcinogenesis (Thapliyal et al. 2003).

Turmeric is also effective against neuronal, cardiac, and kidney disorders. The effect of turmeric on myocardial apoptosis and cardiac function was examined in an ischemia and reperfusion model of myocardial injury. Turmeric at 100 mg/kg administered for 1 month afforded significant cardioprotection and functional recovery that was attributed to reduction in cell death (Mohanty, Arya, and Gupta 2006).

Turmeric is also useful against depression (Yu, Kong, and Chen 2002; Xia et al. 2006; Xia et al. 2007). Its ethanolic extract markedly attenuated swim stress–induced decreases in serotonin, 5-hydroxyindoleacetic acid, and noradrenaline and dopamine concentrations, as well as increases in serotonin turnover. Also, this extract significantly reversed swim stress–induced increases in serum corticotropin-releasing factor and cortisol levels and thus regulated neurochemical and neuroendocrine systems in mice (Xia et al. 2007). In another study, administration of aqueous extracts of turmeric to mice (140–560 mg/kg for 14 days) reduced immobility in the tail suspension test and the forced swimming test (Yu, Kong, and Chen 2002). The effects of 560-mg/kg turmeric were found to be more potent than those of the antidepressant fluoxetine. The extracts significantly inhibited brain monoamine oxidase (MAO)-A activity at a low dose, but at a higher dose, they inhibited brain MAO-B activity. In comparison, fluoxetine showed only a tendency to inhibit MAO-A and -B activity in animal brains. These results demonstrate that turmeric has specific antidepressant effects in vivo. However, since curcumin is not water soluble, the agent in aqueous extracts of turmeric responsible for this activity is not clear.

The antiarthritic effects of turmeric include inhibition of joint inflammation and periarticular joint destruction. In vivo treatment with turmeric extract prevented local activation of NF-κB and the subsequent expression of NF-κB-regulated genes mediating joint inflammation and destruction, including chemokines, COX-2, and the receptor activator of NF-κB ligand (RANKL). It also inhibited inflammatory cell influx, joint levels of PGE2, and periarticular osteoclast formation in rats (Funk et al. 2006). Turmeric was found to be effective against carrageenan-induced edema in rats (Yegnanarayan, Saraf, and Balwani 1976), and water extracts of turmeric were more active than alcohol extracts in the inhibition of carrageenan-induced edema. Turmeric extract, when given intraperitoneally, was found to be more active than hydrocortisone (Ghatak and Basu 1972). The yellow powder of turmeric is known to have potent vasorelaxant activity and to decrease the atherogenic properties of cholesterol. A study showed that supplementation of turmeric in the diet controlled arterial blood pressure in animals and enhanced vasorelaxant responses to adenosine, acetylcholine, and isoproterenol (Zahid Ashraf, Hussain, and Fahim 2005). Turmeric’s antiatherosclerotic effect is associated with inhibition of low-density lipoprotein oxidation, prevention of lipoperoxidation, and reduction in levels of cholesterol (Quiles et al. 1998; Ramírez-Tortosa et al. 1999). A study showed that feeding an ethanolic extract of turmeric to rats elevated the high-density lipoprotein (HDL)-cholesterol/total cholesterol ratio. The extract also caused a significant decrease in the ratio of total cholesterol/phospholipids. Turmeric extract exhibited better cholesterol and triglyceride lowering (85% and 88%, respectively) as compared to Nardostachys jatamansi extract in tritoninduced hyperlipidemic rats (Dixit, Jain, and Joshi 1988). Turmeric suppresses Freund’s adjuvantinduced arthritis and acute edema in rats, and it has also been reported that oil extract of turmeric is more active than cortisone (Chandra and Gupta 1972).

Another interesting property of turmeric is its wound-healing ability. Gujral, Chowdhury, and Saxena (1953) found that turmeric has the property of healing wounds and ulcers in rats and rabbits. Other studies in rabbits revealed that stimulation of mucin secretion could protect the stomach from ulcer (Mukerji, Zaidi, and Singh 1961).

Besides causing these effects, addition of turmeric to the diet significantly improved weight gain of broiler chicks and reduced their relative liver weight. Turmeric also ameliorated the adverse effects of aflatoxin on some serum chemistry parameters (total protein, albumin, cholesterol, calcium) in broiler chicks and restored antioxidant functions in terms of level of peroxides, superoxide dismutase activity, and total antioxidant concentration in their livers (Gowda et al. 2008).

Turmeric acts as a digestive stimulant. As a dietary supplement, it favorably enhanced the activities of pancreatic lipase, chymotrypsin, and amylase. Moreover, turmeric mixed with other spices such as coriander, red chili, black pepper, and cumin brought about a pronounced stimulation of bile flow and bile acid secretion (Platel et al. 2002). Mukerji, Zaidi, and Singh (1961) showed that turmeric increases the mucin content of gastric juice in rabbits. Studies conducted by Farnsworth and Bunyapraphatsara (1992), Supniewski and Hano (1935), and Prucksunand et al. (2001) explain that turmeric has local anesthetic action. After eating turmeric, secretion of gastrin hormone from the antrum of the stomach may be inhibited. Turmeric may possess local membrane-anesthetizing activity at the antrum of the stomach, which then inhibits secretion of gastrin in the same way as oxethazaine, the active ingredient of strocain (Masuda 1973). This is the reason turmeric is administered before meals.

13.6.3. Clinical Studies Using Turmeric

Turmeric has been tested against various diseases in humans (Table 13.5). In one study, the antimutagenic effects of turmeric were examined in 16 chronic smokers (Polasa et al. 1992). Turmeric was given in doses of 1.5 g/day for 30 days, and this was found to significantly reduce the urinary excretion of mutagens in these smokers. In six nonsmokers, on the other hand, no change in urinary excretion of mutagens was noted. These results suggest that dietary turmeric is an effective antimutagen and may be useful in chemoprevention. In another study, the effect of turmeric was examined on patients with irritable bowel syndrome. When 1 or 2 tablets of a standardized turmeric extract were given daily for 8 weeks, the prevalence of irritable bowel syndrome was significantly decreased, as was the abdominal pain/discomfort score (Bundy et al. 2004). Alcoholic extract of turmeric offered protection against BaP-induced increase in micronuclei in circulating lymphocytes of healthy individuals (Hastak et al. 1997). In a subsequent study, the authors treated patients suffering from oral submucous fibrosis (OSF) with turmeric extract (3 g/day) for 3 months. The number of micronuclei from oral exfoliated cells of OSF patients before and after treatment with turmeric extract was recorded. They found that the number of micronuclei in oral exfoliated cells decreased substantially and was comparable with that of normal, healthy individuals (Figure 13.3).

TABLE 13.5

Human Studies with Turmeric.

FIGURE 13.3

Inhibition of micronuclei formation in oral submucous fibrosis (OSF) patients: (a) Incidence of micronuclei in exfoliated buccal mucosal cells of OSF patients before and after treatment with turmeric and of normal healthy individuals. (b) Incidence of (more...)

Turmeric was also found useful in healing peptic ulcers. In a phase II clinical trial, 45 patients with peptic ulcer received capsule-filled turmeric orally in the dose of 2 capsules (300 mg each) five times daily. After 4 weeks of treatment, ulcers were found to be absent in 48% of cases. After 12 weeks of treatment, ulcer-free cases increased to 76% (Prucksunand et al. 2001). A double-blind trial found turmeric to be helpful for people with indigestion and for people with stomach or intestinal ulcers, but it was shown to be less effective than antacids (Kositchaiwat, Kositchaiwat, and Havanondha 1993). An ethanol extract of turmeric was found to produce remarkable symptomatic relief in patients with external cancerous lesions. In a study of 62 patients, reduction in smell was noted in 90% of the cases and reduction of itching in almost all cases. Some patients (10%) had a reduction in lesion size and pain (Kuttan, Sudheeran, and Joseph 1987).

A study on eight healthy subjects showed that the presence of turmeric in curry increases bowel motility and activates hydrogen-producing bacterial flora in the colon, thereby increasing the concentration of breath hydrogen (Shimouchi et al. 2008). Turmeric paste is used to heal wounds or to protect against infection. In certain parts of Bangladesh, turmeric is the most common application on the cut umbilical cord after delivery (Alam et al. 2008).

13.7. STUDIES WITH TURMERIC OIL

Turmeric has medicinal properties due to its bioactive components. One of the important components of turmeric is its volatile oil. The role of turmeric oil in in vitro animals and in human is shown in Table 13.6. Turmeric oil inhibits Trichophyton-induced dermatophytosis in guinea pigs. Apisariyakul, Vanittanakom, and Buddhasukh (1995) showed that 15 different isolates of dermatophytes are inhibited by turmeric oil at dilutions of 1:40 to 1:320. Interestingly, none of the dermatophyte isolates was inhibited by curcumin. Studies of the antiviral effects of the zedoary turmeric oil spray in the respiratory tract showed that whereas influenza virus, parainfluenza viruses I and III, respiratory syncytial virus, and adenoviruses 3 and 7 were inhibited slightly, parainfluenza virus II was significantly inhibited by this turmeric compound (Huang et al. 2007). Curcuma oil ameliorated the ischemia-induced neurological functional deficits and the infarct and edema volumes in rats. It downregulated inducible nitric oxide (NO) synthase (iNOS)-derived NO produced during ischemic injury, which coincided with an increased survival rate of neurons (Dohare et al. 2008). The neuroprotective activity of curcuma oil against cerebral ischemia is associated with its antioxidant activities. Further, cucurma oil attenuated delayed neuronal death via a caspase-dependent pathway. Thus, curcuma oil appears to be a promising agent for the treatment of not only cerebral stroke but also other disorders associated with oxidative stress (Rathore et al. 2008). A study revealed that ingestion of turmeric oleoresin and essential oil inhibits the development of increased blood glucose and abdominal fat mass in obese, diabetic rats (Honda et al. 2006).

TABLE 13.6

Studies with Turmeric Oil.

Turmeric volatile oil is effective against disorders of the respiratory tract. The volatile oil is active in removing sputum, relieving cough, and preventing asthma. Thus, turmeric volatile oil may be an efficacious drug in the treatment of respiratory diseases (Li et al. 1998). This oil acts as a repellent against both day- and night-biting mosquitoes (Tawatsin et al. 2001).

Hexane extracts of C. comosa, an indigenous plant of Thailand that is traditionally used for the treatment of uterine inflammation, at concentrations of 0.1, 0.5, and 1 μM were found to significantly decrease LPS-induced NO and PGE2 production. It also decreased the expression of iNOS and COX-2 (Thampithak et al. 2009).

13.8. SAFETY, EFFICACY, AND CONTRAINDICATIONS

The use of turmeric as a spice and as a household remedy has been known to be safe for centuries. To date, no studies in either animals or humans have discovered any toxic effects associated with the use of turmeric (Lao et al. 2006), and it is clear that turmeric is not toxic even at very high doses. The U.S. Food and Drug Administration (FDA) has conducted its own clinical trials with turmeric and published a 300-page monograph. The FDA has declared turmeric and its active component curcumin as GRAS (generally regarded as safe). Thus, in the United States, turmeric and its components are currently being used in mustard, cereals, chips, cheese, butter, and other products (http://www.kalsec.com/products/color). In a phase I clinical study on the safety and tolerance of turmeric oil use, the oil was administered orally to healthy volunteers for 3 months. No side effects of turmeric oil intake were observed in 3 months on body weight, blood pressure, and hematological, renal, or hepatic toxicity (Joshi et al. 2003).

13.9. CONCLUSIONS

The beneficial effects of turmeric are traditionally achieved through dietary consumption, even at low levels, over long periods of time. A precise understanding of effective dose, safety, and mechanism of action is required for the rational use of turmeric in the treatment of human diseases. Further clinical studies are warranted if turmeric is to be employed in meeting human needs and improving human welfare. The activities of turmeric include antibacterial, antiviral, anti-inflammatory, antitumor, antioxidant, antiseptic, cardioprotective, hepatoprotective, nephroprotective, radioprotective, and digestive activities. Phytochemical analysis of turmeric has revealed a large number of compounds, including curcumin, volatile oil, and curcuminoids, which have been found to have potent pharmacological properties.

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