Oxidation of troglitazone to a quinone-type metabolite catalyzed by cytochrome P-450 2C8 and P-450 3A4 in human liver microsomes.

Yamazaki H, Shibata A, Suzuki M, Nakajima M, Shimada N, Guengerich FP, Yokoi T
Drug Metab Dispos. 1999 27 (11): 1260-6

PMID: 10534310

Troglitazone, a new oral antidiabetic drug, is reported to be mostly metabolized to its conjugates and not to be oxidized by cytochrome P-450 (P-450) enzymes. Of fourteen cDNA-expressed human P-450 enzymes examined, CYP1A1, CYP2C8, CYP2C19, and CYP3A4 were active in catalyzing formation of a quinone-type metabolite at a concentration of 10 microM troglitazone, whereas CYP3A4 had the highest catalytic activity at 100 microM substrate. In human liver microsomes, rates of the quinone-type metabolite formation (at 100 microM) were correlated well with rates of testosterone 6beta-hydroxylation (r = 0.98), but those at 10 microM troglitazone were not correlated with any of several marker activities of P-450 enzymes. Quercetin efficiently inhibited quinone-type metabolite formation (at 10 microM troglitazone) in human samples that contained relatively high levels of CYP2C, whereas ketoconazole affected these activities in liver microsomes in which CYP3A4 levels were relatively high. Anti-CYP2C antibodies strongly inhibited quinone-type metabolite formation (at 10 microM troglitazone) in CYP2C-rich human liver microsomes (by approximately 85%); the intensity of this effect depended on the human samples and their P-450 status. The results suggest that in human liver both CYP2C8 and CYP3A4 have major roles in quinone-type metabolite formation and that the hepatic contents of these two P-450 forms determine which P-450 enzymes play major roles in individual humans. CYP3A4 may be expected to play a role in formation of quinone-type metabolite from troglitazone even at a low concentration in humans.

MeSH Terms (20)

Aryl Hydrocarbon Hydroxylases Catalysis Chromans Cytochrome P-450 CYP2C8 Cytochrome P-450 CYP3A Cytochrome P-450 Enzyme Inhibitors Cytochrome P-450 Enzyme System Enzyme Inhibitors Humans Hypoglycemic Agents Microsomes, Liver Mixed Function Oxygenases Oxidation-Reduction Quinones Recombinant Proteins Steroid 16-alpha-Hydroxylase Steroid Hydroxylases Thiazoles Thiazolidinediones Troglitazone

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