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Research ArticleArticle

Identification of Multiple Glutathione Conjugates of 8-Amino- 2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline maleate (Nomifensine) in Liver Microsomes and Hepatocyte Preparations: Evidence of the Bioactivation of Nomifensine

Jian Yu, Donald E. Mathisen, Doug Burdette, Dean G. Brown, Christopher Becker and David Aharony
Drug Metabolism and Disposition January 2010, 38 (1) 46-60; DOI: https://doi.org/10.1124/dmd.109.028803
Jian Yu
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Donald E. Mathisen
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Doug Burdette
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Dean G. Brown
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Christopher Becker
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David Aharony
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Abstract

8-Amino-2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline maleate (nomifensine), an antidepressant drug, was withdrawn from the market because of increased incidence of hemolytic anemia, as well as kidney and liver toxicity. Although the nature of the potentially reactive metabolites formed after nomifensine metabolism remains unknown and no glutathione (GSH) adducts of these nomifensine reactive metabolites have been reported, bioactivation has been postulated as a potential mechanism for the toxicity of nomifensine. This study was conducted to probe the potential bioactivation pathways of nomifensine in human and animal hepatocytes and in liver microsomes using GSH as a trapping agent. Two types of GSH conjugates were characterized by liquid chromatography/tandem mass spectrometry: 1) aniline oxidation followed by GSH conjugation leading to the formation of nomifensine-GSH sulfinamides (M1 and M2); and 2) arene oxidation followed by GSH conjugation yielding a range of arene C-linked GSH adducts (M3–M9). Nine GSH adducts (M1–M9) were identified in liver microsomes of humans, dogs, monkeys, and rats and in human and rat hepatocytes. In dog hepatocyte preparations, six GSH adducts (M1–M6) were identified. The GSH adducts in dog and rat liver microsomes were formed primarily through aniline and arene oxidation, respectively. Both pathways contributed significantly to the formation of the GSH adducts in human and monkey liver microsomes. The bioactivation pathways proposed here account for the formation of the observed GSH conjugates. These investigations have confirmed the aniline and the arene groups in nomifensine as potential toxicophores capable of generating reactive intermediates.

Footnotes

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

    doi:10.1124/dmd.109.028803

  • ↵Embedded Image The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.

  • Nomifensine
    8-amino-2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline maleate
    GSH
    glutathione
    LC/MS/MS
    liquid chromatography/tandem mass spectrometry
    nomifensine dihydroisoquinolinium perchlorate
    8-amino-2-methyl-4-phenyl-3,4-dihydroisoquinolinium perchlorate
    UPLC
    ultraperformance liquid chromatography
    MS
    mass spectrometry
    CID
    collision-induced dissociation.

    • Received June 5, 2009.
    • Accepted October 6, 2009.
  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 38 (1)
Drug Metabolism and Disposition
Vol. 38, Issue 1
1 Jan 2010
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Identification of Multiple Glutathione Conjugates of 8-Amino- 2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline maleate (Nomifensine) in Liver Microsomes and Hepatocyte Preparations: Evidence of the Bioactivation of Nomifensine
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Research ArticleArticle

Identification of Multiple Glutathione Conjugates of 8-Amino- 2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline maleate (Nomifensine) in Liver Microsomes and Hepatocyte Preparations: Evidence of the Bioactivation of Nomifensine

Jian Yu, Donald E. Mathisen, Doug Burdette, Dean G. Brown, Christopher Becker and David Aharony
Drug Metabolism and Disposition January 1, 2010, 38 (1) 46-60; DOI: https://doi.org/10.1124/dmd.109.028803

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Research ArticleArticle

Identification of Multiple Glutathione Conjugates of 8-Amino- 2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline maleate (Nomifensine) in Liver Microsomes and Hepatocyte Preparations: Evidence of the Bioactivation of Nomifensine

Jian Yu, Donald E. Mathisen, Doug Burdette, Dean G. Brown, Christopher Becker and David Aharony
Drug Metabolism and Disposition January 1, 2010, 38 (1) 46-60; DOI: https://doi.org/10.1124/dmd.109.028803
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