Transcriptional regulation of the rat glutathione S-transferase Ya subunit gene. Characterization of a xenobiotic-responsive element controlling inducible expression by phenolic antioxidants.

We have identified previously a xenobiotic-responsive element, which we termed the beta-naphthoflavone-responsive element, between nucleotide -722 and -682 in the 5'-flanking region of the rat glutathione S-transferase Ya subunit gene (Rushmore, T.H., King, R.G., Paulson, K.E., and Pickett, C.B. (1990) Proc. Natl. Acad. Sci. U.S.A. 87, 3826-3830). The beta-naphthoflavone-responsive element is responsible for part of the transcriptional activation of the Ya subunit gene by planar aromatic compounds but has a sequence distinct from the xenobiotic-responsive element found in multiple copies in the cytochrome P-450 IA1 gene and as a single copy in the Ya subunit gene. In the present study, we demonstrate that the beta-naphthoflavone-responsive element is required for the transcriptional activation of the Ya subunit gene by phenolic antioxidants such as t-butylhydroquinone through a mechanism that does not require functional Ah receptors. Furthermore, we present evidence that planar aromatic compounds must be metabolized before they transcriptionally activate the Ya subunit gene through the beta-naphthoflavone-responsive element. The transcriptional activation of the Ya subunit gene by planar aromatic compounds requires a functional Ah receptor. These data provide evidence that transcriptional activation of the glutathione S-transferase Ya subunit gene can be mediated by a novel xenobiotic-responsive element which is directly responsive to phenolic antioxidants such as t-butylhydroquinone. Hence we have named this new xenobiotic-responsive element the antioxidant-responsive element or ARE.