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.
Rushmore
T H
TH
Merck Frosst Centre for Therapeutic Research, Pointe-Claire-Dorval, Quebec, Canada.
Pickett
C B
CB
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001483:Base Sequence; D001571:Benzoflavones / Q000494:pharmacology*; D002460:Cell Line; D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics; D002872:Chromosome Deletion; D005419:Flavonoids / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic; D005809:Genes, Regulator / Q000187:drug effects; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D046911:Macromolecular Substances; D008969:Molecular Sequence Data; D009154:Mutation; D015345:Oligonucleotide Probes; D010636:Phenols / Q000494:pharmacology*; D051381:Rats; D015183:Restriction Mapping; D014158:Transcription, Genetic; D014162:Transfection; D019324:beta-Naphthoflavone
D000975:Antioxidants; D001571:Benzoflavones; D005419:Flavonoids; D046911:Macromolecular Substances; D015345:Oligonucleotide Probes; D010636:Phenols; D019324:beta-Naphthoflavone; D015500:Chloramphenicol O-Acetyltransferase; D005982:Glutathione Transferase