TY - JOUR T1 - 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. AU - Yu,Jian, AU - Mathisen,Donald E, AU - Burdette,Doug, AU - Brown,Dean G, AU - Becker,Christopher, AU - Aharony,David, PY - 2009/10/9/entrez PY - 2009/10/9/pubmed PY - 2010/3/20/medline SP - 46 EP - 60 JF - Drug metabolism and disposition: the biological fate of chemicals JO - Drug Metab Dispos VL - 38 IS - 1 N2 - 8-Amino-2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline maleate (nomifensine), an antidepressant drug, was withdrawn from the market because of increased incidence of hemolytic anemia, as well as kidney and liver toxicity.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. SN - 1521-009X UR - https://www.unboundmedicine.com/medline/citation/19812352/Identification_of_multiple_glutathione_conjugates_of_8_amino__2_methyl_4_phenyl_1234_tetrahydroisoquinoline_maleate__nomifensine__in_liver_microsomes_and_hepatocyte_preparations:_evidence_of_the_bioactivation_of_nomifensine_ L2 - http://dmd.aspetjournals.org/cgi/pmidlookup?view=long&pmid=19812352 DB - PRIME DP - Unbound Medicine ER -