Document Detail


Involvement of Different Human Glutathione S-transferase Isoforms in the Glutathione Conjugation of Reactive Metabolites of Troglitazone.
MedLine Citation:
PMID:  21914835     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Null mutation of both glutathione S-transferase (GST) M1 and GSTT1 was reported to correlate statistically with an abnormal increase in the plasma levels of ALT or AST caused by troglitazone in the diabetic patients (Watanabe I et al., Clin Pharmacol Ther, 73, 435-55 (2003)). This clinical evidence leads to the hypothesis whereby glutathione (GSH) conjugation catalyzed by GSTT1 and GSTM1 has a role in the elimination of reactive metabolites of troglitazone. However, the contribution of GST isoforms expressed in human liver to the detoxification of reactive metabolites of troglitazone has not yet been clarified. We investigated the involvement of human GST isoforms in GSH conjugation of reactive metabolites of troglitazone using recombinant GST enzymes. Five reported GSH conjugates of reactive metabolites were produced from troglitazone after incubation with liver microsomes, nicotinamide adenine dinucleotide phosphate (NADPH) and GSH in a GSH concentration-dependent manner. Addition of human recombinant GSTA1, GSTA2, GSTM1 or GSTP1 protein to the incubation mixture further increased the GSH conjugates. However, the addition of GSTT1 did not show any catalytic effect. Interestingly, one of the reactive metabolites with a quinone structure was predominantly conjugated with GSH by GSTM1. Thus, we demonstrated that the GST isoforms contributed differently to GSH conjugation of individual reactive metabolites of troglitazone, and GSTM1 is the most important GST isoform in GSH conjugation of a specific reactive metabolite produced from the cytotoxic, quinone-form metabolite of troglitazone.
Authors:
Ran Okada; Kazuya Maeda; Takahito Nishiyama; Shinsuke Aoyama; Zenzaburo Tozuka; Akira Hiratsuka; Toshihiko Ikeda; Hiroyuki Kusuhara; Yuichi Sugiyama
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-9-13
Journal Detail:
Title:  Drug metabolism and disposition: the biological fate of chemicals     Volume:  -     ISSN:  1521-009X     ISO Abbreviation:  -     Publication Date:  2011 Sep 
Date Detail:
Created Date:  2011-9-14     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9421550     Medline TA:  Drug Metab Dispos     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
1 Graduate School of Pharmaceutical Sciences, The University of Tokyo;
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