Sulfotransferase Expression: Implications for Toxicity

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EXCEED THE SPACE PROVIDED. The hydroxysteroid sulfotransferase (SULT2A) enzymes detoxify drugs, xenobiotics, mono-hydroxy bile acids, and bioactivate hydroxy methyl polycyclic aromatic hydrocarbon carcinogens in toxicant target tissues such as the liver. Because sulfated steroids are generally receptor inactive, SULT2A enzymes also function as pivotal hormone- deactivating enzymes in the liver, and have the distinctive capacity to modulate the expression of hormone- responsive genes. The principal SULT2A isoform in rat liver is SULT2A-40/41. We have new evidence in support of a novel and complex dual control mechanism in the transcriptionalregulation of glucocorticoid-inducible SULT2A-40/41, and have identified the critical c/s-acting gene sequences in SULT2A-40/41 that control glucocorticoid-inducible expression by both physiological (glucocorticoid receptor-saturating concentrations)and pharmacological doses of glucocorticoid (concentrations of steroid that prevail during the stress response and would be expected to activate alternative nuclear receptors). In addition, we have established that in adult male mouse hepatocytes, the functional homolog of SULT2A-40/41 undergoes programmed gene silencing as a consequence of mechanisms that are insensitive to treatment with the potent histone deacetylaseinhibitor, trichostatin A, suggesting that epigenetic mechanisms regulate the expression of this gene during development. The hypothesis of the proposed research is three-fold. (1) The induction of rat hepatic SULT2A-40/41 gene expression by physiological concentrations of glucocorticoid occurs as a consequence of glucocorticoid- receptor-mediated induction of liver-enriched transcription factors (such as C/EBP and HNF-1), which then bind to consensus sequences in the proximal S'-flanking region of the SULT2A-40/41 gene and activate transcription. (2) Pharmacological doses of dexamethasone activate an orphan member of the nuclear receptor superfamily, which then binds to a c/s-acting inverted repeat element with zero intervening bases (IRO) in a more distal portion of the 5'-flanking region of the SULT2A-40/41 gene and activate gene transcription. (3) In male mouse hepatocytes, the silencing of basal and glucocorticoid-inducible SULT2A gene expression is produced by the programmed hypermethylation of critical CpG dinucleotides in the mouse STI|LT2A gene.