Induction of AP-1 (Fos/Jun) by chemical agents mediates activation of glutathione S-transferase and quinone reductase gene expression.

A regulatory element, EpRE, was found to be responsible for the induction of mouse glutathione S-transferase (GST) Ya gene expression by a variety of chemical agents such as planar aromatic hydrocarbons, diphenols, phorbol ester, phenobarbital and electrophilic compounds. The EpRE 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 this 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/Jun complex. The activation of GST Ya and quinone reductase genes by a variety of chemical inducers is found to be associated with an increase in AP-1 binding activity. We present evidence that chemical agents induce expression of c-fos and c-jun proto-oncogenes and an enhanced synthesis of protein components of AP-1 complex. We suggest that the increased synthesis of AP-1 complex followed by an AP-1-mediated transcriptional activation of GST Ya and quinone reductase genes may provide a molecular mechanism for the induction of these drug-metabolizing enzymes by chemical agents.