This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ireson, C. Articles by Gescher, A. Search for Related Content PubMed PubMed Citation Articles by Ireson, C. Articles by Gescher, A.

Characterization of Metabolites of the Chemopreventive Agent Curcumin in Human and Rat Hepatocytes and in the Rat in Vivo, and Evaluation of Their Ability to Inhibit Phorbol Ester-induced Prostaglandin E₂ Production¹

Medical Research Council Toxicology Unit [C. I., D. J. L. J., R. V., C-K. L., J-L. L., L. H., S. P., R. J., A. G.] and Department of Oncology [M. W., W. P. S.], University of Leicester, Leicester LE1 9HN, and School of Pharmacy and Pharmaceutical Sciences, De-Montfort University, Leicester LE1 9BH [S. O.], United Kingdom

Curcumin, the yellow pigment in turmeric, has been shown to prevent malignancies in a variety of tissues in rodents, especially in the intestinal tract. Pharmacological activities of curcumin in cells in situ germane to chemoprevention, such as inhibition of expression of cyclooxygenase-2 (COX-2), require drug concentrations in the 10^-5–10^-4 M range. The systemic bioavailability of curcumin is low, so that its pharmacological activity may be mediated, in part, by curcumin metabolites. To investigate this possibility, we compared curcumin metabolism in human and rat hepatocytes in suspension with that in rats in vivo. Analysis by high-performance liquid chromatography with detection at 420 and 280 nm permitted characterization of metabolites with both intact diferoylmethane structure and increased saturation of the heptatrienone chain. Chromatographic inferences were corroborated by mass spectrometry. The major metabolites in suspensions of human or rat hepatocytes were identified as hexahydrocurcumin and hexahydrocurcuminol. In rats, in vivo, curcumin administered i.v. (40 mg/kg) disappeared from the plasma within 1 h of dosing. After p.o. administration (500 mg/kg), parent drug was present in plasma at levels near the detection limit. The major products of curcumin biotransformation identified in rat plasma were curcumin glucuronide and curcumin sulfate whereas hexahydrocurcumin, hexahydrocurcuminol, and hexahydrocurcumin glucuronide were present in small amounts. To test the hypothesis that curcumin metabolites resemble their progenitor in that they can inhibit COX-2 expression, curcumin and four of its metabolites at a concentration of 20 µM were compared in terms of their ability to inhibit phorbol ester-induced prostaglandin E₂ (PGE₂) production in human colonic epithelial cells. Curcumin reduced PGE₂ levels to preinduction levels, whereas tetrahydrocurcumin, previously shown to be a murine metabolite of curcumin, hexahydrocurcumin, and curcumin sulfate, had only weak PGE₂ inhibitory activity, and hexahydrocurcuminol was inactive. The results suggest that (a) the major products of curcumin biotransformation by hepatocytes occur only at low abundance in rat plasma after curcumin administration; and (b) metabolism of curcumin by reduction or conjugation generates species with reduced ability to inhibit COX-2 expression. Because the gastrointestinal tract seems to be exposed more prominently to unmetabolized curcumin than any other tissue, the results support the clinical evaluation of curcumin as a colorectal cancer chemopreventive agent.

This article has been cited by other articles:

				S.J. Moghaddam, P. Barta, S.G. Mirabolfathinejad, Z. Ammar-Aouchiche, N. T. Garza, T.T. Vo, R. A. Newman, B. B. Aggarwal, C. M. Evans, M. J. Tuvim, et al. Curcumin inhibits COPD-like airway inflammation and lung cancer progression in mice Carcinogenesis, November 1, 2009; 30(11): 1949 - 1956. [Abstract] [Full Text] [PDF]

				A. Koeberle, H. Northoff, and O. Werz Curcumin blocks prostaglandin E2 biosynthesis through direct inhibition of the microsomal prostaglandin E2 synthase-1 Mol. Cancer Ther., August 1, 2009; 8(8): 2348 - 2355. [Abstract] [Full Text] [PDF]

				S. S. Ghosh, H. D. Massey, R. Krieg, Z. A. Fazelbhoy, S. Ghosh, D. A. Sica, I. Fakhry, and T. W. B. Gehr Curcumin ameliorates renal failure in 5/6 nephrectomized rats: role of inflammation Am J Physiol Renal Physiol, May 1, 2009; 296(5): F1146 - F1157. [Abstract] [Full Text] [PDF]

				Y.-I. Jeong, S. W. Kim, I. D. Jung, J. S. Lee, J. H. Chang, C.-M. Lee, S. H. Chun, M.-S. Yoon, G. T. Kim, S. W. Ryu, et al. Curcumin Suppresses the Induction of Indoleamine 2,3-Dioxygenase by Blocking the Janus-activated Kinase-Protein Kinase C{delta}-STAT1 Signaling Pathway in Interferon-{gamma}-stimulated Murine Dendritic Cells J. Biol. Chem., February 6, 2009; 284(6): 3700 - 3708. [Abstract] [Full Text] [PDF]

				N. Dhillon, B. B. Aggarwal, R. A. Newman, R. A. Wolff, A. B. Kunnumakkara, J. L. Abbruzzese, C. S. Ng, V. Badmaev, and R. Kurzrock Phase II Trial of Curcumin in Patients with Advanced Pancreatic Cancer Clin. Cancer Res., July 15, 2008; 14(14): 4491 - 4499. [Abstract] [Full Text] [PDF]

				A. N. Begum, M. R. Jones, G. P. Lim, T. Morihara, P. Kim, D. D. Heath, C. L. Rock, M. A. Pruitt, F. Yang, B. Hudspeth, et al. Curcumin Structure-Function, Bioavailability, and Efficacy in Models of Neuroinflammation and Alzheimer's Disease J. Pharmacol. Exp. Ther., July 1, 2008; 326(1): 196 - 208. [Abstract] [Full Text] [PDF]

				S. K. Vareed, M. Kakarala, M. T. Ruffin, J. A. Crowell, D. P. Normolle, Z. Djuric, and D. E. Brenner Pharmacokinetics of Curcumin Conjugate Metabolites in Healthy Human Subjects Cancer Epidemiol. Biomarkers Prev., June 1, 2008; 17(6): 1411 - 1417. [Abstract] [Full Text] [PDF]

				Y. Zeng, F. Qiu, Y. Liu, G. Qu, and X. Yao Isolation and Identification of Phase 1 Metabolites of Demethoxycurcumin in Rats Drug Metab. Dispos., September 1, 2007; 35(9): 1564 - 1573. [Abstract] [Full Text] [PDF]

				C. Tamvakopoulos, K. Dimas, Z. D. Sofianos, S. Hatziantoniou, Z. Han, Z.-L. Liu, J. H. Wyche, and P. Pantazis Metabolism and Anticancer Activity of the Curcumin Analogue, Dimethoxycurcumin Clin. Cancer Res., February 15, 2007; 13(4): 1269 - 1277. [Abstract] [Full Text] [PDF]

				Y. Moon, W. C. Glasgow, and T. E. Eling Curcumin Suppresses Interleukin 1{beta}-Mediated Microsomal Prostaglandin E Synthase 1 by Altering Early Growth Response Gene 1 and Other Signaling Pathways J. Pharmacol. Exp. Ther., November 1, 2005; 315(2): 788 - 795. [Abstract] [Full Text] [PDF]

				H. Cai, M. Al-Fayez, R. G. Tunstall, S. Platton, P. Greaves, W. P. Steward, and A. J. Gescher The rice bran constituent tricin potently inhibits cyclooxygenase enzymes and interferes with intestinal carcinogenesis in ApcMin mice Mol. Cancer Ther., September 1, 2005; 4(9): 1287 - 1292. [Abstract] [Full Text] [PDF]

				G. Garcea, D. P. Berry, D. J.L. Jones, R. Singh, A. R. Dennison, P. B. Farmer, R. A. Sharma, W. P. Steward, and A. J. Gescher Consumption of the Putative Chemopreventive Agent Curcumin by Cancer Patients: Assessment of Curcumin Levels in the Colorectum and their Pharmacodynamic Consequences Cancer Epidemiol. Biomarkers Prev., January 1, 2005; 14(1): 120 - 125. [Abstract] [Full Text] [PDF]

				R. A. Sharma, S. A. Euden, S. L. Platton, D. N. Cooke, A. Shafayat, H. R. Hewitt, T. H. Marczylo, B. Morgan, D. Hemingway, S. M. Plummer, et al. Phase I Clinical Trial of Oral Curcumin: Biomarkers of Systemic Activity and Compliance Clin. Cancer Res., October 15, 2004; 10(20): 6847 - 6854. [Abstract] [Full Text] [PDF]

				Curcumin Derivatives: Potential for Prostate Cancer Management: ADDANKI P. KUMAR, GRETCHEN E. GARCIA, RITA GHOSH, RAJENDRAN V. RAJNARAYANAN,1 WILLIAM L. ALWORTH,1 AND THOMAS J. SLAGA, Center for Cancer Causation and Prevention, AMC Cancer Research Center and University of Colorado Comprehensive Cancer Center, Denver, Colorado 80214; 1 Department of Chemistry, Tulane University, New Orleans, Louisiana 70118 Toxicol Pathol, January 1, 2004; 32(1): 161 - 163. [PDF]

				J. W Lampe Spicing up a vegetarian diet: chemopreventive effects of phytochemicals Am. J. Clinical Nutrition, September 1, 2003; 78(3): 579S - 583. [Abstract] [Full Text] [PDF]

				I. Gukovsky, C. N. Reyes, E. C. Vaquero, A. S. Gukovskaya, and S. J. Pandol Curcumin ameliorates ethanol and nonethanol experimental pancreatitis Am J Physiol Gastrointest Liver Physiol, January 1, 2003; 284(1): G85 - G95. [Abstract] [Full Text] [PDF]

				N. Li, X. Chen, J. Liao, G. Yang, S. Wang, Y. Josephson, C. Han, J. Chen, M.-T. Huang, and C. S. Yang Inhibition of 7,12-dimethylbenz[a]anthracene (DMBA)-induced oral carcinogenesis in hamsters by tea and curcumin Carcinogenesis, August 1, 2002; 23(8): 1307 - 1313. [Abstract] [Full Text] [PDF]

				S. Somasundaram, N. A. Edmund, D. T. Moore, G. W. Small, Y. Y. Shi, and R. Z. Orlowski Dietary Curcumin Inhibits Chemotherapy-induced Apoptosis in Models of Human Breast Cancer Cancer Res., July 1, 2002; 62(13): 3868 - 3875. [Abstract] [Full Text] [PDF]

				S. Perkins, R. D. Verschoyle, K. Hill, I. Parveen, M. D. Threadgill, R. A. Sharma, M. L. Williams, W. P. Steward, and A. J. Gescher Chemopreventive Efficacy and Pharmacokinetics of Curcumin in the Min/+ Mouse, a Model of Familial Adenomatous Polyposis Cancer Epidemiol. Biomarkers Prev., June 1, 2002; 11(6): 535 - 540. [Abstract] [Full Text] [PDF]

				C. R. Ireson, D. J. L. Jones, S. Orr, M. W. H. Coughtrie, D. J. Boocock, M. L. Williams, P. B. Farmer, W. P. Steward, and A. J. Gescher Metabolism of the Cancer Chemopreventive Agent Curcumin in Human and Rat Intestine Cancer Epidemiol. Biomarkers Prev., January 1, 2002; 11(1): 105 - 111. [Abstract] [Full Text]

				S. M. Plummer, K. A. Hill, M. F. W. Festing, W. P. Steward, A. J. Gescher, and R. A. Sharma Clinical Development of Leukocyte Cyclooxygenase 2 Activity as a Systemic Biomarker for Cancer Chemopreventive Agents Cancer Epidemiol. Biomarkers Prev., December 1, 2001; 10(12): 1295 - 1299. [Abstract] [Full Text] [PDF]

				A. Asai and T. Miyazawa Dietary Curcuminoids Prevent High-Fat Diet-Induced Lipid Accumulation in Rat Liver and Epididymal Adipose Tissue J. Nutr., November 1, 2001; 131(11): 2932 - 2935. [Abstract] [Full Text] [PDF]

				R. A. Sharma, H. R. McLelland, K. A. Hill, C. R. Ireson, S. A. Euden, M. M. Manson, M. Pirmohamed, L. J. Marnett, A. J. Gescher, and W. P. Steward Pharmacodynamic and Pharmacokinetic Study of Oral Curcuma Extract in Patients with Colorectal Cancer Clin. Cancer Res., July 1, 2001; 7(7): 1894 - 1900. [Abstract] [Full Text] [PDF]

				R. A. Sharma, C. R. Ireson, R. D. Verschoyle, K. A. Hill, M. L. Williams, C. Leuratti, M. M. Manson, L. J. Marnett, W. P. Steward, and A. Gescher Effects of Dietary Curcumin on Glutathione S-Transferase and Malondialdehyde-DNA Adducts in Rat Liver and Colon Mucosa: Relationship with Drug Levels1 Clin. Cancer Res., May 1, 2001; 7(5): 1452 - 1458. [Abstract] [Full Text]