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Research ArticleArticle

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

Hiroshi Yamazaki, Ayaka Shibata, Mikie Suzuki, Miki Nakajima, Noriaki Shimada, F. Peter Guengerich and Tsuyoshi Yokoi
Drug Metabolism and Disposition November 1999, 27 (11) 1260-1266;
Hiroshi Yamazaki
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Ayaka Shibata
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Mikie Suzuki
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Miki Nakajima
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Noriaki Shimada
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F. Peter Guengerich
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Tsuyoshi Yokoi
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Abstract

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.

Footnotes

  • Send reprint requests to: Hiroshi Yamazaki, Ph.D., Division of Drug Metabolism, Faculty of Pharmaceutical Sciences, Kanazawa University, 13–1 Takara-machi, Kanazawa 920-0934, Japan. E-mail: yamazak{at}kenroku.kanazawa-u.ac.jp

  • Supported in part by grants from the Ministry of Education, Science, Sports, and Culture of Japan, and the Ministry of Health and Welfare of Japan.

  • Abbreviations used are::
    P-450
    cytochrome P-450
    b5
    cytochromeb5
    CuOOH
    cumene hydroperoxide
    metabolite 3
    (±)-5-[4-[2-hydroxy-2-methyl-4-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)butoxy]benzyl]-2,4-thiazolidinedione
    • Received March 30, 1999.
    • Accepted July 9, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 27 (11)
Drug Metabolism and Disposition
Vol. 27, Issue 11
1 Nov 1999
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Research ArticleArticle

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

Hiroshi Yamazaki, Ayaka Shibata, Mikie Suzuki, Miki Nakajima, Noriaki Shimada, F. Peter Guengerich and Tsuyoshi Yokoi
Drug Metabolism and Disposition November 1, 1999, 27 (11) 1260-1266;

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Research ArticleArticle

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

Hiroshi Yamazaki, Ayaka Shibata, Mikie Suzuki, Miki Nakajima, Noriaki Shimada, F. Peter Guengerich and Tsuyoshi Yokoi
Drug Metabolism and Disposition November 1, 1999, 27 (11) 1260-1266;
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