title: 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 production.
abstract: 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 microM 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.
authors.affiliation: Medical Research Council Toxicology Unit, University of Leicester, United Kingdom.
authors.forename: C
authors.initials: C
authors.lastname: Ireson
authors.forename: S
authors.initials: S
authors.lastname: Orr
authors.forename: D J
authors.initials: DJ
authors.lastname: Jones
authors.forename: R
authors.initials: R
authors.lastname: Verschoyle
authors.forename: C K
authors.initials: CK
authors.lastname: Lim
authors.forename: J L
authors.initials: JL
authors.lastname: Luo
authors.forename: L
authors.initials: L
authors.lastname: Howells
authors.forename: S
authors.initials: S
authors.lastname: Plummer
authors.forename: R
authors.initials: R
authors.lastname: Jukes
authors.forename: M
authors.initials: M
authors.lastname: Williams
authors.forename: W P
authors.initials: WP
authors.lastname: Steward
authors.forename: A
authors.initials: A
authors.lastname: Gescher
mesh_terms: D000328:Adult; D000818:Animals; D016588:Anticarcinogenic Agents / Q000378:metabolism* / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D003106:Colon / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D003474:Curcumin / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000096:biosynthesis*; D004347:Drug Interactions; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D020719:Glucuronides / Q000378:metabolism* / Q000494:pharmacology; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D013058:Mass Spectrometry; D008565:Membrane Proteins; D008875:Middle Aged; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D013755:Tetradecanoylphorbol Acetate / Q000037:antagonists & inhibitors* / Q000494:pharmacology
chemical_list: D016588:Anticarcinogenic Agents; D020719:Glucuronides; D007527:Isoenzymes; D008565:Membrane Proteins; C000591193:curcumin glucuronide; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D003474:Curcumin; D015232:Dinoprostone; D013755:Tetradecanoylphorbol Acetate