Curcuma (Tumeric): Biological Activity and Active Compounds - ACS

Chapter 11

Curcuma (Tumeric): Biological Activity and Active Compounds

Downloaded by UNIV OF PITTSBURGH on May 4, 2015 | http://pubs.acs.org Publication Date: April 15, 1998 | doi: 10.1021/bk-1998-0691.ch011

M. Wichtl Institute of Pharmaceutical Biology, Department of Pharmacy, Philipps-University, D-35032 Marburg, Germany

Extracts of Curcuma domestica and Curcuma xanthorrhiza rhizomes (turmeric, Javanese turmeric resp.) are used in Europe as cholagogues. In Eastern Asia only C. xanthorrhiza is in use for the treatment of biliary disorders. The active compounds, diarylheptanes, esp. curcuminoids, and constituents of the essential oils, mainly sesquiterpenes, have been—and are still—objects of pharmacological and clinical studies. Many interesting effects, such as antiinflammatory, lipid reducing, and sedative actions, have been reported. Nevertheless, more research is necessary to better understand the mechanism of action of Javanese turmeric. Biliary disorders and their therapy are an important part of the practice of family doctors and specialists for internal diseases. In addition to several synthetic drugs, some phytopharmaceuticals are therapeutically used in Europe. The most effective are those prepared from the rhizomes of two Curcuma species, turmeric and Javanese turmeric. Remedies to cure biliary disorders are (less exactly) named cholagogues. They are differentiated into choleretics (raise the production of bjle) and cholekinetics (stimulate the contraction and emptying of the gall bladder). Both remedies are used in the therapy of cholecystitis and cholangitis, or generally to stimulate production of bile, but they are contraindicated for gallstones or hepatitis. Curcuma xanthorrhiza (Javanese turmeric) and Curcuma domestica (syn. C. longa, turmeric) are perennial herbs, belonging to the Zingiberaceae family and are cultivated in Indonesia and South India. The very large, oblong lanceolate leaves show a more or less parallel nervature. The zygomorphic flowers appear at ground level and have three fused sepals and three large yellow petals, with only one fertile stamen The rhizomes of both species are more or less tuberousovoid, in case of C. domestica also cylindrical or fingershaped. When the rhizomes of C.domestica are scalded with boiling water in toto, the starch becomes largely gelatinized and the surface turns an intensive yellow. The rhizome of Curcuma xanthorrhiza is purified superficially and

©1998 American Chemical Society

In Phytomedicines of Europe; Lawson, L., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1998.

133

134 then cut into small slices of about 3 mm thickness. The rhizomes of Javanese turmeric have been used in Indonesia medicinally for centuries under the name „Temu lavak" as a cholagogue. This remedy was made known in Europe by the Dutch, the former colonizers of Indonesia, and was (and is still) official in the Nederlandse Pharmacopoeia. Since 1978, Curcumae xanthorrhizae rhizoma has been official in the German Pharmacopoeia as well In contrast to the Javanese turmeric, Curcuma domestica has been used in tropical Asia only as a spice (it is one of the component parts of Curry powder), not as a remedy. In Germany this Curcuma species is also used as a cholagogue, since it has very similar constituents.


Constituents The rhizomes of both Curcuma species contain (a) diarylheptane-derivatives, esp. the "curcuminoids, dicinnamoylmethane-derivatives, and (b) essential oil, comprising mainly sesquiterpenes. Turmeric, Curcumae domesticae rhizoma, contains 3-5% yellow pigments that are not volatile in steam; diarylheptanoids, consisting mainly of three compounds, curcumin (diferuloylmethane), monodesmethoxycurcumin (feruloyl-phydroxycinnamoylmethane) and bisdesmethoxycurcumin (7); and 2-7% essential oil, comprising sesquiterpenes of the germacrane-, bisabolane- and guajane-types. The main compounds of the volatile oil are turmerone, ar-turmerone, zingiberene and curlone. The high content of bisabolane derivatives is characteristic for turmeric and cannot be observed in other Curcuma species (2). Currently, more than 100 constituents have been isolated and their structures elucidated by spectral methods. Turmeric also contains small amounts of a complex acidic arabinogalactan, ukonan A (3) and starch, largely gelatinized. Javanese turmeric, Curcumae xanthorrhizae rhizoma, contains only 1-2% diarylheptanoids (curcuminoids), mainly curcumin and monodesmethoxycurcumin (7, 4), but the content of essential oil, 3-12%, is higher than that of C. domestica. The essential oil comprises mainly sesquiterpenes, such as P-curcumene, ar-curcumene, germacrone, and a phenolic sesquiterpene xanthorrhizol, a characteristic constituent of this drug. p-Tolylmethylcarbinol, earlier described as a compound of the essential oil, is no doubt an artefact, which arises during the distillation of the oil. ,,

Pharmacological and Clinical Investigations The use of both plant drugs for the treatment of biliary disorders, such as chronic forms of cholangitis and cholecystitis, has been confirmed by some pharmacological and clinical investigations (5-8). Therefore, in Germany many preparations, prepared from the rhizomes of both Curcuma species, are licensed by the Institute for Remedies (the government health agency). The German Commission E has published monographs for both plant drugs, with the indication "dyspeptic complaints." For the efficacy of the extracts, prepared from these Curcuma species, both the curcuminoids and the essential oils are responsible. The curcuminoids act mainly as cholekinetics, but they also stimulate the choleresis. Extracts of C. xanthorrhiza are distinctly more effective than extracts of C. domestica, in accordance with the empirical medicinal use



135

0

0

R

Curcumin DesmethoxycurcumJn Bisdesmethoxycurcumin

(3-Turmerone

Scheme 1.

R

1

OCH OCH H

3 3

2

OCH H H

Curlone

3

Zingiberene

Germacrone

Scheme 2.


136 in Indonesia. Maybe the choleresis-inhibiting property, described for bisdesmethoxycurcumin (present only in C. domestica), is responsible for this phenomenon (7). Between 1992 and 1996 some interesting pharmacological effects of isolated, pure constituents were reported. Curcumin, the main constituted of both Curcumaspecies, parenterally administered, acts strongly as an antiphlogistic and inhibits the formation of leukotriene B , a mediator-substance of inflammation (9). The in vitro inhibition of prostaglandin biosynthesis by curcumin had been observed earlier by H.Wagner and coworkers (70). Curcumin demonstrates in vitro effects on the biosynthesis of prostacyclin and on platelet aggregation in rats and in monkey plasma (77). Evaluation of nonsteroidal anti-inflammatory drugs in patients with postoperative inflammation produced an anti-inflammatory response for curcumin at the same level as phenylbutazone (72). Experiments on rats to find out the oral resorption of curcumin showed the major biliary metabolites were glucuronides of tetrahydro- and hexahydrocurcumin (13). Antiphlogistic effects have also been recently detected for some the phenolic and nonphenolic diarylheptanoids, as well as for trans-trans-l,7-diphenyl-l,3heptadien-5-one (alnustone), trans-l,7-diphenyl-l-hepten-5-ol, and trans-trans-1,7diphenyl-l,3-heptadien-5-ol (14). An ethanolic extract of turmeric, as well as an ointment of curcumin (0.5% curcumin), were found to produce remarkable symptomatic relief in patients with external cancerous lesions after application of the ointment three times daily for four weeks; in many patients the effect continued for several months (75). Also, in studies on experimentally induced skin tumors in mouse (induction by 12-0tetradecanonylphorbol-13-acetat) curcumin was found to markedly inhibit tumor promotion: topical application of 1, 3 or 10 pmol of curcumin inhibited the induced tumors by 39, 77 or 98% respectively (16). The antitumor activity of curcumin is probably related to the inhibition of a phospholipid-dependent protein kinase C (PKC), because some other inhibitors of PKC can also inhibit tumor promotion caused by phorbol esters (77, 18). Recent investigations demonstrate the activity of curcumin at a molecular level Treatment of human myeloid M L - l a cells with tumor necrosis factor rapidly activated the transcription factor NF-kB, and this activation was inhibited by curcumin (79, 20). In an other experiment, it could be demonstrated that curcumin inhibits the phorbolester-induced expression of c-fos, c-jun, and c-myc protooncogenes messenger R N A (27). Curcumin, at 5 p M , inhibited in vitro lipopolysaccharide-induced production of TNF (tumor necrosis factor a) and interleukin-ip by a human monocytic macrophage cell line, Mono Mac. 6 (22). For some diarylheptanoids a hypolipidemic action, evaluated in Triton-induced hyperlipidemic hamsters by inhibiting hepatic triglyceride secretion, has been reported (23). Besides curcumin, the most effective compounds were 5-hydroxy-7(4hydroxyphenyl)-1 -phenyl-( IE)-1 -heptene and 7-(3,4-dihydroxyphenyl)-5-hydroxy-1 phenyl-(lE)-l-heptene, the latter being more potent than the former, but there is up to now no practical use of this observation. A very interesting discovery was made in 1995 with evidence of anti-HIVactivity for curcumin. On purified human HTV-1 integrase, curcumin was shown to


4


trans-trans-1,7-diphenyl-l

,3-heptadien-4-one


OH

trans-1,7-diphenyl-l-hepten-5-ol

OH

trans, trans-1,7-diphenyl-l,

3-heptadien-5-ol

Scheme 3.

5-hydroxy-7-(4-hy droxy phenyl)-1 -phenyl-( 1E)-1 -heptene OH

7-(3,4-dihydroxyphenyl)-5-hydroxy-l-phenyl-{l£)-l-heptene Scheme 4.


138 have an inhibitory concentration (I ) for strand transfer of 40 p M , probably interacting with the integrase catalytic core (24). Also, for some constituents of the essential oils, remarkable pharmacological effects have been demonstrated. Xanthorrhizol, the species-specific compound of Javanese turmeric, acts as a sedative: oral administration to mice at 50 mg/kg, xanthorrhizol prolongated the pentobarbital-induced sleeping time (328%), and its activity was almost the same as that of chlorpromazine at 5 mg/kg (25). Germacrone, a sesquiterpene-ketone of Cxanthorrhizja, upon oral administration to mice at 100200 mg/kg, showed a significant hypothermic effect ( AT ca 2-2.8° C) (26). At least nine sesquiterpenes of the essential oil of Curcuma xanthorrhiza, (e.g. xanthorrhizol, fiiranodienone, and others) are very effective contact-insecticides (27). Many other pharmacodynamic studies have been published in a review by H.P.T.Ammon et aL (28). Most of the demonstrated activities have not (or not yet) been clinically demonstrated. Nevertheless a European patent was granted for a fixed combination of Cwrcwma-constituents as an antiphlogistic (29), and a Japanese patent was granted for germacrone (30) as a component part of an CNS-depressant remedy. Besides their use as cholagogues, both Curcuma species should demand an increasing interest as sources of medicinally useful substances.


50

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Curcuma (Tumeric): Biological Activity and Active Compounds - ACS

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