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Research ArticleArticle

Formation of a Novel Quinone Epoxide Metabolite of Troglitazone with Cytotoxic to HepG2 Cells

Yui Yamamoto, Hiroshi Yamazaki, Tomoko Ikeda, Terumi Watanabe, Haruo Iwabuchi, Miki Nakajima and Tsuyoshi Yokoi
Drug Metabolism and Disposition February 2002, 30 (2) 155-160; DOI: https://doi.org/10.1124/dmd.30.2.155
Yui Yamamoto
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Hiroshi Yamazaki
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Tomoko Ikeda
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Terumi Watanabe
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Haruo Iwabuchi
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Miki Nakajima
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Tsuyoshi Yokoi
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Abstract

Troglitazone, an oral antidiabetic drug, was reported to cause adverse hepatic effects in certain individuals, leading to its withdrawal from the market. After incubation of troglitazone (100 μM) with the human hepatoma cell line, HepG2 cells, and human primary hepatocytes for 48 to 72 h, an unknown peak was detected in the cell culture. The formation of this peak from troglitazone (100 μM) was also catalyzed by expressed CYP3A4, and further HPLC analysis revealed that there were three metabolites (metabolite A, B, and C) in the peak. The major metabolite, metabolite C (M-C) was identified as an epoxide of a quinone metabolite of troglitazone by comparison with a synthetic authentic standard using tandem mass spectrometry,1H NMR, and 13C NMR analyses. The other two metabolites (M-A and M-B) were stereoisomers with the same molecular weight as M-C, probably produced from M-C by intramolecular rearrangement at the epoxide moiety. M-C showed a weak cytotoxicity in HepG2 cells at low concentrations, as assessed by the crystal violet-staining assay. Since epoxides are generally regarded as the chemically reactive species, M-C may play a role in idiosyncrasy of troglitazone hepatotoxicity via individual differences either in the formation or degradation of this metabolite.

Footnotes

  • Supported in part by a grant from Takeda Science Foundation.

  • Abbreviations used are::
    GSH
    glutathione
    MS/MS
    tandem mass spectrography
    P450
    cytochrome P450
    NPR
    NADPH-cytochrome P450 reductase
    b5
    cytochromeb5
    HPLC
    high-performance liquid chromatography
    Q-TOF
    quadrupole time-of-flight
    ESI
    electrospray ionization
    LC
    liquid chromatography
    • Received July 2, 2001.
    • Accepted November 6, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 30 (2)
Drug Metabolism and Disposition
Vol. 30, Issue 2
1 Feb 2002
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Research ArticleArticle

Formation of a Novel Quinone Epoxide Metabolite of Troglitazone with Cytotoxic to HepG2 Cells

Yui Yamamoto, Hiroshi Yamazaki, Tomoko Ikeda, Terumi Watanabe, Haruo Iwabuchi, Miki Nakajima and Tsuyoshi Yokoi
Drug Metabolism and Disposition February 1, 2002, 30 (2) 155-160; DOI: https://doi.org/10.1124/dmd.30.2.155

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Research ArticleArticle

Formation of a Novel Quinone Epoxide Metabolite of Troglitazone with Cytotoxic to HepG2 Cells

Yui Yamamoto, Hiroshi Yamazaki, Tomoko Ikeda, Terumi Watanabe, Haruo Iwabuchi, Miki Nakajima and Tsuyoshi Yokoi
Drug Metabolism and Disposition February 1, 2002, 30 (2) 155-160; DOI: https://doi.org/10.1124/dmd.30.2.155
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