INTRACELLULAR GLUTATHIONE LEVELS REGULATE FOS JUN INDUCTION AND ACTIVATION OF GLUTATHIONE-S-TRANSFERASE GENE-EXPRESSION

Induction of glutathione S-transferase Ya and NAD(P)H:quinone reductas e gene expression by a variety of chemical agents is mediated by regul atory elements, EpRE and ARE, composed of two adjacent AP-1-like bindi ng sites and activated by Fos/Jun heterodimeric complex (AP-1). Recent studies show that chemical induction of glutathione S transferase Ya and quinone reductase gene expression is associated with an induction of C-fos and c-jun gene expression and AP-1 binding activity. In this report we present evidence that the AP-1 binding activity and the expr ession of chloramphenicol acetyltransferase activity from an EpRE Ya-c at gene construct are induced by an increase in intracellular oxidant levels. We observe that lowering the glutathione levels with buthionin e sulfoximine, an inhibitor of gamma-glutamylcysteine synthetase, or d iamide, a thiol-oxidizing agent, stimulates both basal and chemical-in ducible expression of chloramphenicol acetyltransferase activity from EpRE Ya-cat and the AP-1 binding activity. Furthermore, we observe tha t the induction of these activities by a variety of chemical agents is inhibited by thiol compounds N-acetylcysteine and glutathione. These findings suggest that diverse chemicals that induce the AP-1 complex, leading to the AP-1-mediated transcriptional activation of glutathione S-transferase Ya gene expression, may act through a common mechanism involving the production of reactive oxygen species and depletion of r educed glutathione.