RT Journal Article SR Electronic T1 Oxidation of Troglitazone to a Quinone-Type Metabolite Catalyzed by Cytochrome P-450 2C8 and P-450 3A4 in Human Liver Microsomes JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 1260 OP 1266 VO 27 IS 11 A1 Hiroshi Yamazaki A1 Ayaka Shibata A1 Mikie Suzuki A1 Miki Nakajima A1 Noriaki Shimada A1 F. Peter Guengerich A1 Tsuyoshi Yokoi YR 1999 UL http://dmd.aspetjournals.org/content/27/11/1260.abstract AB 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 μM troglitazone, whereas CYP3A4 had the highest catalytic activity at 100 μM substrate. In human liver microsomes, rates of the quinone-type metabolite formation (at 100 μM) were correlated well with rates of testosterone 6β-hydroxylation (r = 0.98), but those at 10 μM troglitazone were not correlated with any of several marker activities of P-450 enzymes. Quercetin efficiently inhibited quinone-type metabolite formation (at 10 μM 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 μM troglitazone) in CYP2C-rich human liver microsomes (by ∼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. The American Society for Pharmacology and Experimental Therapeutics