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
2001
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
E 2 (PGE 2 ) production in human colonic
epithelial cells. Curcumin reduced PGE 2 levels to
preinduction levels, whereas tetrahydrocurcumin, previously shown to be
a murine metabolite of curcumin, hexahydrocurcumin, and curcumin
sulfate, had only weak PGE 2 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.
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