title: Involvement of different human glutathione transferase isoforms in the glutathione conjugation of reactive metabolites of troglitazone.
abstract: Null mutation of glutathione transferase (GST) M1 and GSTT1 was reported to correlate statistically with an abnormal increase in the plasma levels of alanine aminotransferase or aspartate aminotransferase caused by troglitazone in diabetic patients (Clin Pharmacol Ther, 73:435-455, 2003). This clinical evidence leads to the hypothesis that 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 the 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, 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. It is of interest that 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 the GSH conjugation of individual reactive metabolites of troglitazone, and GSTM1 is the most important GST isoform in the GSH conjugation of a specific reactive metabolite produced from the cytotoxic, quinone-form metabolite of troglitazone.
authors.affiliation: Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
authors.forename: Ran
authors.initials: R
authors.lastname: Okada
authors.forename: Kazuya
authors.initials: K
authors.lastname: Maeda
authors.forename: Takahito
authors.initials: T
authors.lastname: Nishiyama
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Aoyama
authors.forename: Zenzaburo
authors.initials: Z
authors.lastname: Tozuka
authors.forename: Akira
authors.initials: A
authors.lastname: Hiratsuka
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Ikeda
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kusuhara
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Sugiyama
mesh_terms: D002384:Catalysis; D002839:Chromans / Q000378:metabolism*; D002853:Chromatography, Liquid; D005978:Glutathione / Q000378:metabolism*; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism*; D008862:Microsomes, Liver / Q000201:enzymology; D009154:Mutation; D053719:Tandem Mass Spectrometry; D045162:Thiazolidinediones / Q000378:metabolism*; D000077288:Troglitazone
chemical_list: D002839:Chromans; D007004:Hypoglycemic Agents; D007527:Isoenzymes; D045162:Thiazolidinediones; D005982:Glutathione Transferase; D005978:Glutathione; D000077288:Troglitazone