Involvement of Different Human Glutathione Transferase Isoforms in the Glutathione Conjugation of Reactive Metabolites of Troglitazone

Abstract

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.

Demethylation of neferine in human liver microsomes and formation of quinone methide metabolites mediated by CYP3A4 accentuates its cytotoxicity

“…It is noted that the three GST isoforms participated in the formation of each reactive metabolite of neferine only to a limited degree. In contrast to the significant catalytic role of GST isoforms in the formation of the quinone-form metabolite of troglitazone [31], here, we speculate that the null mutation of GSTT1 isoforms would not increase idiosyncratic drug-induced liver injury (DILI).…”

Formation of A Novel Purine Metabolite through CYP3A4 Bioactivation and Glutathione Conjugation

“…Glutathione conjugation is a common metabolic reaction involved in the metabolism and clearance of xenobiotics. The formation of this conjugated metabolite could be through instantaneous reaction with an activated intermediate or facilitated by glutathione S-transferase [ 13 , 14 ]. Unexpected glutathione conjugated metabolites have previously been investigated and reported on different scaffolds [ 15 ].…”

Regulation of Glutathione in Health and Disease with Special Emphasis on Chronic Alcoholism and Hyperglycaemia Mediated Liver Injury: A Brief Perspective

“…The null mutation of GSTM1 and GSTT1 is reported to correlate statistically with an abnormal increase in the plasma levels of alanine aminotransferase or aspartate aminotransferase caused by troglitazone in diabetic patients [119]. The involvement of the human GST isoforms in the GSH conjugation of reactive metabolites of troglitazone using recombinant GST enzymes has been investigated [88]. Five reported GSH conjugates of reactive metabolites are produced from troglitazone after incubation with liver microsomes, NADPH, and GSH in a GSH concentration-dependent manner [88].…”

“…The involvement of the human GST isoforms in the GSH conjugation of reactive metabolites of troglitazone using recombinant GST enzymes has been investigated [88]. Five reported GSH conjugates of reactive metabolites are produced from troglitazone after incubation with liver microsomes, NADPH, and GSH in a GSH concentration-dependent manner [88]. The addition of human recombinant GSTA1, GSTA2, GSTM1 or GSTP1 protein to the incubation mixture further increases the GSH conjugates [88].…”

“…Five reported GSH conjugates of reactive metabolites are produced from troglitazone after incubation with liver microsomes, NADPH, and GSH in a GSH concentration-dependent manner [88]. The addition of human recombinant GSTA1, GSTA2, GSTM1 or GSTP1 protein to the incubation mixture further increases the GSH conjugates [88]. Thus, the GST isoforms contribute 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 [88].…”