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

• DOI: 10.1124/dmd.111.040469
• Publication Date: 2011-09-14T04:12:48Z
• Authors: Ran Okada; Kazuya Maeda; Takahito Nishiyama; Shinsuke Aoyama; Zenzaburo Tozuka; Akira Hiratsuka; Toshihiko Ikeda; Hiroyuki Kusuhara; Yuichi Sugiyama
• Keywords: Troglitazone

Null mutation of glutathione transferase (<i>GST</i>) <i>M1</i> and <i>GSTT1</i> was reported to correlate statistically with an abnormal increase in the plasma levels alanine aminotransferase or aspartate caused by troglitazone diabetic patients (<i>Clin Pharmacol Ther</i>, 73:435–455, 2003). This clinical evidence leads hypothesis that GSH conjugation catalyzed GSTT1 GSTM1 has a role elimination reactive metabolites troglitazone. However, contribution GST isoforms expressed human liver detoxification not yet been clarified. We investigated involvement using recombinant enzymes. Five conjugates were produced from after incubation microsomes, NADPH, concentration-dependent manner. Addition GSTA1, GSTA2, GSTM1, GSTP1 protein mixture further increased conjugates. addition did show any catalytic effect. It is interest one quinone structure predominantly conjugated GSTM1. Thus, we demonstrated contributed differently individual troglitazone, most important isoform specific metabolite cytotoxic, quinone-form