Microsomal glutathione-S-transferase 1 activation in relation to the cytochrome P450 system

The specific activity of MGST1 was increased significantly (0.3-fold, P < 0 .05) in the presence of an NADPH-regenerating system as compared with contr ols without NADPH in isolated rat liver microsomes. An inhibitor of CYP2E1, 4-methylpyrazole, significantly prevented the MGST1 activation. Several co mpounds/enzymes that inhibit the generation of, or scavenge reactive oxygen species did not show significant prevention of MGST1 activation, except GS H and dithiothreitol (DTT) (60 and 80%, respectively, P<0.05). Since neithe r added superoxide (KO2) nor hydrogen peroxide (H2O2) stimulated MGST1, act ivation did not appear to be a simple effect of reactive oxygen species onl y. Our data indicate that an NADPH dependent process can activate MGST1 via the sulfhydryl group of Cys-49. In addition, the activation appears to inv olve multiple mechanisms possibly including several reduced oxygen species and CYP2E1. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.