Regulation of Rat Hepatic Hydroxysteroid Sulfotransferase (SULT2-40/41) Gene Expression by Glucocorticoids: Evidence for a Dual Mechanism of Transcriptional Control

Runge‐Morris, Melissa; Wu, Wei; Kocarek, Thomas A.

doi:10.1124/mol.56.6.1198

Cited by 70 publications

(62 citation statements)

References 26 publications

(36 reference statements)

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“…A subset of orphan nuclear receptors, specifically the bile acid activated farnesoid X receptor (FXR) and steroid-and xenobiotic-activated pregnane X receptor (PXR), are tran-scriptional inducers of Sult2A1 in the liver and intestine (Runge-Morris et al, 1999;Song et al, 2001;Echchgadda et al, 2002;Sonoda et al, 2002). A corresponding increase in the enzyme activity has also been observed.…”

mentioning

confidence: 96%

Dehydroepiandrosterone Sulfotransferase Is a Target for Transcriptional Induction by the Vitamin D Receptor

Song²,

et al. 2004

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Dehydroepiandrosterone sulfotransferase (SULT2A1) is a cytosolic enzyme that mediates sulfo-conjugation of endogenous hydroxysteroids (dehydroepiandrosterone, testosterone, bile acids), and diverse xenobiotic compounds. Upon sulfonation, SULT2A1 substrates become polar and water-soluble and thus suitable for rapid excretion. SULT2A1 is abundantly expressed in the liver and intestine. Recent evidence has shown that the ligand-activated vitamin D receptor (VDR) can transcriptionally induce the xenobiotic-metabolizing cytochrome P450 enzymes. Herein, we report that VDR also targets SULT2A1 for transcriptional activation. Vitamin D stimulated endogenous SULT2A1 expression and induced transfected human, mouse, and rat SULT2A1 promoters in liver and intestinal cells upon cotransfection with VDR. An inverted repeat DNA element (IR0), located within Ϫ191 to Ϫ168 positions of mouse and rat Sult2A1, mediates VDR induction of Sult2A1. DNase1 footprinting, competition EMSA, and antibody supershift assay showed that the IR0 is a binding site for the RXR-␣/VDR heterodimer. Point mutations within the IR0 prevented RXR/VDR binding and abolished VDR-mediated Sult2A1 induction. The IR0 element conferred VDR responsiveness on a thymidine kinase promoter. Thus, VDR-mediated nuclear signaling may be important in the phase II metabolism involving Sult2A1. The rodent Sult2A1 gene is also induced by the farnesoid X receptor (FXR) and pregnane X receptor (PXR) through the same IR0. In competition transfections, FXR or PXR inhibited VDR induction of the IR0. Competitive functional interactions among VDR, PXR, and FXR suggest that the intracellular hormonal and metabolic milieu may determine the extent to which a specific nuclear receptor pathway would influence steroid/xenobiotic metabolism using dehydroepiandrosterone sulfotransferase.

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confidence: 96%

Dehydroepiandrosterone Sulfotransferase Is a Target for Transcriptional Induction by the Vitamin D Receptor

Song²,

et al. 2004

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“…Sequence analysis of the rodent SULT2A gene promoters revealed an IR-0 (inverted repeats without a spacing nucleotide) type of nuclear receptor response element (Fig. 4A) (Runge-Morris et al, 1999;Song et al, 2001;Sonoda et al, 2002). The rat 2A1/IR0 element was shown to bind to and mediate the transactivation by PXR (Sonoda et al, 2002) and FXR (Song et al, 2001).…”

Section: Car Induces Sulfotransferases and Bile Acid Detoxificationmentioning

confidence: 99%

“…The expression of rodent SULT has been shown to be induced by PB and TCPOBOP, two reported CAR agonists (Runge-Morris et al, 1999;Garcia-Allan et al, 2000;Maglich et al, 2002). Having established that activation of CAR is sufficient to induce SULT2A9, we went on to examine whether xenobiotic receptors, such as CAR and PXR, are necessary for the ligand-dependent activation of SULT.…”

Section: Car Induces Sulfotransferases and Bile Acid Detoxificationmentioning

confidence: 99%

“…Although CAR has been well characterized as a cytochrome P450 gene regulator, no direct evidence that relates the function of this xenobiotic receptor to the transcriptional activation of SULT is available. PB and TCPOBOP have been shown to induce members of the SULT family, although the molecular basis remains to be defined (Runge-Morris et al, 1999;Garcia-Allan et al, 2000;Maglich et al, 2002). Both PB and TCPOBOP are efficacious CAR activators, suggesting this as a plausible signaling pathway for SULT transcription.…”

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confidence: 99%

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A Novel Constitutive Androstane Receptor-Mediated and CYP3A-Independent Pathway of Bile Acid Detoxification

Saini

Sonoda²,

Xu³

et al. 2004

Mol Pharmacol

230

178

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Cytosolic sulfotransferase (SULT)-mediated sulfation plays an essential role in the detoxification of bile acids and is necessary to avoid pathological conditions, such as cholestasis, liver damage, and colon cancer. In this study, using transgenic mice bearing conditional expression of the activated constitutive androstane receptor (CAR), we demonstrate that activation of CAR is both necessary and sufficient to confer resistance to the hepatotoxicity of lithocholic acid (LCA). Surprisingly, the CARmediated protection is not attributable to the expected and previously characterized CYP3A pathway; rather, it is associated with a robust induction of SULT gene expression and increased LCA sulfation. We have also provided direct evidence that CAR regulates SULT expression by binding to the CAR response elements found within the SULT gene promoters. Interestingly, activation of CAR was also associated with an increased expression of the 3Ј-phosphoadenosine 5Ј-phosphosulfate synthetase 2 (PAPSS2), an enzyme responsible for generating the sulfate donor 3Ј-phosphoadenosine-5Ј-phosphosulfate. Analysis of gene knockout mice revealed that CAR is also indispensable for ligand-dependent activation of SULT and PAPSS2 in vivo. Therefore, we establish an essential and unique role of CAR in controlling the mammalian sulfation system and its implication in the detoxification of bile acids.

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“…SULTs induction by hormones and other endogenous molecules has been relatively well known (Liu and Klaassen, 1996;Duanmu et al, 2001;Dunn and Klaassen, 2000;Klaassen et al, 1998;RungeMorris, 1998;Runge-Morris et al, 1999;Wu et al, 2001;Runge-Morris and Kocarek, 2005). Xenobiotic induction of SULTs is not well studied.…”

Section: Introductionmentioning

confidence: 99%

Methamphetamine Regulation of Sulfotransferases in Rat Liver and Brain

Zhou¹

2010

American Journal of Pharmacology and Toxicology

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Problem statement: Sulfotransferases (SULTs) are important phase II drug metabolizing enzymes. They also regulate the biological activities of various hormones. To the best of our knowledge, psychostimulants regulation of SULTs is basically not studied except one article reported that Methamphetamine (METH) treatment induced rat amygdale rSULT1A1 mRNA 4.3 fold by using microarray method to identify a series of candidate genes after single-dose METH treatment. The psychostimulant METH is used to treat disorders such as attention deficit, narcolepsy and obesity. It is also a highly addictive drug that causes serious social problems. The abuse of this drug leads to the damage of monoaminergic systems in the mammalian brain. It is important to understand how SULT expressions are regulated by psychostimulants. Approach: This study was performed to evaluate the effect of METH on SULT gene expressions in rat liver and brain. METH (0, 1, 5, 20 mg kg −1 day −1 ) was used to treat male and female rats for 7 days by oral administration. Rat livers and brains were collected 24 h after the final drug treatment. Western blot and real-time RT-PCR were used to investigate the effect of METH on SULT protein and mRNA expression, respectively, in rat liver and brain. Results: Proteins and mRNAs of rSULT1A1, rSULT2A1 and rSULT1E1 were induced in liver and brain of both male and female rats following METH treatment. rSULT1E1 was induced at much higher level compared to that of rSULT1A1 and rSULT2A1. Brain inductions were found to be much higher than those found in liver. Conclusion: These data suggest an important role of the central dopaminergic system in the regulation of liver and brain rSULT expressions.

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Regulation of Rat Hepatic Hydroxysteroid Sulfotransferase (SULT2-40/41) Gene Expression by Glucocorticoids: Evidence for a Dual Mechanism of Transcriptional Control

Cited by 70 publications

References 26 publications

Dehydroepiandrosterone Sulfotransferase Is a Target for Transcriptional Induction by the Vitamin D Receptor

Dehydroepiandrosterone Sulfotransferase Is a Target for Transcriptional Induction by the Vitamin D Receptor

A Novel Constitutive Androstane Receptor-Mediated and CYP3A-Independent Pathway of Bile Acid Detoxification

Methamphetamine Regulation of Sulfotransferases in Rat Liver and Brain

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