Oxidation of Troglitazone to a Quinone-Type Metabolite Catalyzed by Cytochrome P-450 2C8 and P-450 3A4 in Human Liver Microsomes

• Published in: Drug metabolism and disposition Vol. 27; no. 11; pp. 1260 - 1266
• Main Authors: YAMAZAKI, H, SHIBATA, A, SUZUKI, M, NAKAJIMA, M, SHIMADA, N, GUENGERICH, F. P, YOKOI, T
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Society for Pharmacology and Experimental Therapeutics 01-11-1999
• Subjects: Aryl Hydrocarbon Hydroxylases; Biological and medical sciences; Catalysis; Chromans - metabolism; Cytochrome P-450 CYP2C8; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System - metabolism; Enzyme Inhibitors - pharmacology; General and cellular metabolism. Vitamins; Humans; Hypoglycemic Agents - metabolism; Medical sciences; Microsomes, Liver - enzymology; Microsomes, Liver - metabolism; Mixed Function Oxygenases - antagonists & inhibitors; Mixed Function Oxygenases - metabolism; Oxidation-Reduction; Pharmacology. Drug treatments; Quinones - metabolism; Recombinant Proteins - metabolism; Steroid 16-alpha-Hydroxylase; Steroid Hydroxylases - antagonists & inhibitors; Steroid Hydroxylases - metabolism; Thiazoles - metabolism; Thiazolidinediones; Troglitazone; Human; Unspecific monooxygenase; Enzyme; Digestive system; Isozyme; Cytochrome P450; Liver; Metabolism; In vitro; Hypoglycemic agent; Enzymatic activity; Drug-metabolizing enzyme; Oxidation; Oxidoreductases; Troglitazone
• ISSN: 0090-9556; 1521-009X

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.