INDUCTION OF AP-1 (FOS JUN) BY CHEMICAL-AGENTS MEDIATES ACTIVATION OFGLUTATHIONE-S-TRANSFERASE AND QUINONE REDUCTASE GENE-EXPRESSION/

A regulatory element, EpRE, was found to be responsible for the induct ion of mouse glutathione S-transferase (GST) Ya gene expression by a v ariety of chemical agents such as planar aromatic hydrocarbons, diphen ols, phorbol ester, phenobarbital and electrophilic compounds. The EpR E is composed of two adjacent AP-1-like binding sites and was recently found to be activated by Fos/Jun heterodimeric complex (AP-1). In thi s report we show that regulatory elements ARE, previously demonstrated to mediate the chemical induction of rat GST Ya and quinone reductase genes, have a similar structure with EpRE and are activated by Fos/Ju n complex. The activation of GST Ya and quinone reductase genes by a v ariety of chemical inducers is found to be associated with an increase in AP-1 binding activity. We present evidence that chemical agents in duce expression of c-fos and c-jun proto-oncogenes and an enhanced syn thesis of protein components of AP-1 complex. We suggest that the incr eased synthesis of AP-1 complex followed by an AP-l-mediated transcrip tional activation of GST Ya and quinone reductase genes may provide a molecular mechanism for the induction of these drug-metabolizing enzym es by chemical agents.