| 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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MedLine Citation:
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PMID: 19812352 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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8-Amino-2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline maleate (nomifensine), an antidepressant drug, was withdrawn from the market because of increased incidence of hemolytic anemia, as well as kidney and liver toxicity.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. |
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Authors:
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Jian Yu; Donald E Mathisen; Doug Burdette; Dean G Brown; Christopher Becker; David Aharony |
Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: Drug metabolism and disposition: the biological fate of chemicals Volume: 38 ISSN: 1521-009X ISO Abbreviation: Drug Metab. Dispos. Publication Date: 2010 Jan |
Date Detail:
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Created Date: 2009-12-16 Completed Date: 2010-03-19 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9421550 Medline TA: Drug Metab Dispos Country: United States |
Other Details:
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Languages: eng Pagination: 46-60 Citation Subset: IM |
Affiliation:
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Department of Discovery Drug Metabolism and Pharmacokinetics, AstraZeneca Pharmaceuticals LP, 1800 Concord Pike, L-260C, P.O. Box 15437, Wilmington, DE 19850-5437, USA. jian.yu@astrazeneca.com |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Biotransformation / physiology Chromatography, Liquid Dogs Fourier Analysis Glutathione / metabolism* Hepatocytes / metabolism* Humans Macaca fascicularis Microsomes, Liver / metabolism* Models, Chemical Molecular Structure Molecular Weight NADP / metabolism Nomifensine / analogs & derivatives, metabolism, pharmacokinetics* Rats Rats, Sprague-Dawley Tandem Mass Spectrometry |
| Chemical | |
Reg. No./Substance:
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24526-64-5/Nomifensine; 53-59-8/NADP; 70-18-8/Glutathione |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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