RT Journal Article
SR Electronic
T1 Involvement of Different Human Glutathione Transferase Isoforms in the Glutathione Conjugation of Reactive Metabolites of Troglitazone
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 2290
OP 2297
DO 10.1124/dmd.111.040469
VO 39
IS 12
A1 Ran Okada
A1 Kazuya Maeda
A1 Takahito Nishiyama
A1 Shinsuke Aoyama
A1 Zenzaburo Tozuka
A1 Akira Hiratsuka
A1 Toshihiko Ikeda
A1 Hiroyuki Kusuhara
A1 Yuichi Sugiyama
YR 2011
UL http://dmd.aspetjournals.org/content/39/12/2290.abstract
AB 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.