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Research ArticleArticle

Identification of a Novel Glutathione Conjugate of Flutamide in Incubations with Human Liver Microsomes

Ping Kang, Deepak Dalvie, Evan Smith, Sue Zhou and Alan Deese
Drug Metabolism and Disposition July 2007, 35 (7) 1081-1088; DOI: https://doi.org/10.1124/dmd.107.014860
Ping Kang
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Deepak Dalvie
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Evan Smith
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Sue Zhou
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Alan Deese
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Abstract

Flutamide, a nonsteroidal antiandrogen drug widely used in the treatment of prostate cancer, has been associated with rare incidences of hepatotoxicity in patients. It is believed that bioactivation of flutamide and subsequent covalent binding to cellular proteins is responsible for its toxicity. Current in vitro studies were undertaken to probe the cytochrome P450 (P450)-mediated bioactivation of flutamide and identify the possible reactive species using reduced glutathione (GSH) as a trapping agent. NADPH- and GSH-supplemented human liver microsomal incubations of flutamide gave rise to a novel GSH conjugate where GSH moiety was conjugated to the flutamide molecule via the amide nitrogen, resulting in a sulfenamide. The structure of the conjugate was characterized by liquid chromatography-tandem mass spectrometry and NMR experiments. The conjugate formation was primarily catalyzed by heterologously expressed CYP2C19, CYP1A2, and, to a lesser extent, CYP3A4 and CYP3A5. The mechanism for the formation of this conjugate is unknown; however, a tentative bioactivation mechanism involving a P450-catalyzed abstraction of hydrogen atom from the amide nitrogen of flutamide and the subsequent trapping of the nitrogen-centered radical by GSH or oxidized glutathione (GSSG) was proposed. Interestingly, the same adduct was formed when flutamide was incubated with human liver microsomes in the presence of GSSG and NADPH. This finding suggests that P450-mediated oxidation of flutamide via a nitrogen-centered free radical could be one of the several bioactivation pathways of flutamide. Even though the relationship of the GSH conjugate to flutamide-induced toxicity is unknown, the results have revealed the formation of a novel, hitherto unknown, GSH adduct of flutamide.

Footnotes

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.107.014860.

  • ABBREVIATIONS: flutamide, 2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]-propanamide; GSH, reduced glutathione; GSSG, oxidized glutathione; LC, liquid chromatography; MS, mass spectrometry; MS/MS, tandem mass spectrometry; FLU-1, 4-nitro-3-(trifluoromethyl)phenylamine; P450, cytochrome P450; HPLC, high-performance liquid chromatography; COSY, correlation spectroscopy; amu, atomic mass units.

  • ↵1 Current affiliation: Genentech, Inc., South San Francisco, California.

    • Received January 24, 2007.
    • Accepted March 28, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 35 (7)
Drug Metabolism and Disposition
Vol. 35, Issue 7
1 Jul 2007
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Research ArticleArticle

Identification of a Novel Glutathione Conjugate of Flutamide in Incubations with Human Liver Microsomes

Ping Kang, Deepak Dalvie, Evan Smith, Sue Zhou and Alan Deese
Drug Metabolism and Disposition July 1, 2007, 35 (7) 1081-1088; DOI: https://doi.org/10.1124/dmd.107.014860

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Research ArticleArticle

Identification of a Novel Glutathione Conjugate of Flutamide in Incubations with Human Liver Microsomes

Ping Kang, Deepak Dalvie, Evan Smith, Sue Zhou and Alan Deese
Drug Metabolism and Disposition July 1, 2007, 35 (7) 1081-1088; DOI: https://doi.org/10.1124/dmd.107.014860
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