Regulation of Sulfotransferases by Xenobiotic Receptors

M.      Runge-Morris; T.   A.   Kocarek

doi:10.2174/1389200054633871

Abstract

The transcription factor networks that regulate basal and xenobiotic-modulated expression of the hepatic sulfotransferases affect the dynamics of xenobiotic detoxication, carcinogen bioactivation and metabolic homeostasis. Emerging evidence suggests that liver-enriched transcription factors, the aryl hydrocarbon (Ah) receptor and members of the nuclear receptor transcription factor superfamily all play integrated roles in the control of sulfotransferase gene transcription. Unlike the well known up-regulation of CYP1A1, expression of rat hepatic aryl (SULT1A1) and hydroxysteroid (SULT2A) sulfotransferase is suppressed in response to treatment with the prototypic Ah receptor ligand, 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin. Glucocorticoid-inducible rat hepatic SULT1A1 gene transcription occurs through a glucocorticoid receptor (GR)-mediated mechanism, while human hepatic SULT1A1 does not display GRinducible expression. By comparison, liver-enriched transcription factors, such as CCAAT/enhancer binding protein, are essential for the maintenance of basal and GR-inducible rat hepatic SULT2A expression. The transcriptional control of rodent and human hepatic SULT2A expression is subject to trans-activation by the environmental sensor, pregnane X receptor (PXR). IR0 (inverted repeat with zero intervening bases) motifs located in the 5-flanking regions of rodent SULT2A genes are required for transcriptional activation by PXR and other nuclear receptors, including constitutive androstane receptor, farnesoid X receptor and vitamin D receptor. Peroxisome proliferator activated receptor α (PPARα) mediates the induction of human, but not rat, hepatic SULT2A gene transcription, thus implicating a role for fatty acids as endogenous regulators of hepatic sulfonation in humans. This review focuses on the xenobiotic sensors and transcription factor systems that regulate sulfotransferase gene expression.

Keywords: sulfotransferase, xenobiotic, glucocorticoid receptor, pregnane x receptor, constitutive androstane receptor, peroxisome proliferator-activated receptor

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