Inhibition of Sulfotransferases by Xenobiotics

Wang, Liquan; James, Margaret O.

doi:10.2174/138920006774832596

Cited by 131 publications

(93 citation statements)

References 148 publications

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“…SULT activity may be inhibited in humans exposed to certain therapeutic drugs, dietary or environmental chemicals 67 . The inhibitory effects of various compounds have been examined mainly for the SULT1A subfamily.…”

Section: Sults: Forms Tissue and Cellular Distributionmentioning

confidence: 99%

Phase Ii Drug Metabolizing Enzymes

Jančová¹,

Anzenbacher²,

2010

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Section: Sults: Forms Tissue and Cellular Distributionmentioning

confidence: 99%

Phase Ii Drug Metabolizing Enzymes

Jančová¹,

Anzenbacher²,

2010

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“…Sulfotransferases (SULTs) are one of the major superfamily of phase II drug metabolizing enzymes (Bojarova and Williams, 2008;Chapman et al, 2004;Gamage et al, 2006;Hempel et al, 2007;Kauffman, 2004;Rath et al, 2004;Runge-Morris and Kocarek, 2005;Wang and James, 2006). They catalyze the sulfation of hydroxyl-containing compounds.…”

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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“…The technique is expected to translate well to other systems and, in particular, to other SULT isoforms, where SULT1A1 will be used to obtain structures of the binding sites of other putative SULT allosteres, which include the potent inhibition of SULT1A1 by NSAIDs (10, 11); the allosteric regulation of SULT2A1 by celecoxib, an FDA-approved anticancer drug that changes the substrate specificity of the enzyme (49); and the potent inhibition of SULT1E1 by polychlorinated hydroxyl-bisphenols (OH-PCBs)-the putative basis for the endocrine disruptions caused by these environmental toxins (50,51). Beyond using the method in the current study to decipher how, at the molecular level, allosteres control SULT catalytic function lies the important issue of how such insights might be used to deepen our understanding of SULT biology.…”

Section: Discussionmentioning

confidence: 99%

The structure of the catechin-binding site of human sulfotransferase 1A1

Cook

Wang

Girvin

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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We are just beginning to understand the allosteric regulation of the human cytosolic sulfotransferase (SULTs) family-13 disease-relevant enzymes that regulate the activities of hundreds, if not thousands, of signaling small molecules. SULT1A1, the predominant isoform in adult liver, harbors two noninteracting allosteric sites, each of which binds a different molecular family: the catechins (naturally occurring flavonols) and nonsteroidal antiinflammatory drugs (NSAIDs). Here, we present the structure of an SULT allosteric binding site-the catechin-binding site of SULT1A1 bound to epigallocatechin gallate (EGCG). The allosteric pocket resides in a dynamic region of the protein that enables EGCG to control opening and closure of the enzyme's active-site cap. Furthermore, the structure offers a molecular explanation for the isozyme specificity of EGCG, which is corroborated experimentally. The bindingsite structure was obtained without X-ray crystallography or multidimensional NMR. Instead, a SULT1A1 apoprotein structure was used to guide positioning of a small number of spin-labeled single-Cys mutants that coat the entire enzyme surface with a paramagnetic field of sufficient strength to determine its contribution to the bound ligand's transverse (T 2 ) relaxation from its 1D solution spectrum. EGCG protons were mapped to the protein surface by triangulation using the T 2 values to calculate their distances to a trio of spin-labeled Cys mutants. The final structure was obtained using distance-constrained molecular dynamics docking. This approach, which is readily extensible to other systems, is applicable over a wide range of ligand affinities, requires little protein, avoids the need for isotopically labeled protein, and has no protein molecular weight limitations.sulfotransferase | structure | NMR | allostery | catechin C ytosolic SULTs regulate disease-relevant process in virtually every tissue in the human body (1-5). This small family of broadspecificity enzymes regulates the activities of hundreds, perhaps thousands, of signaling small molecules (e.g., endogenous metabolites, drugs, and other xenobiotics) via regiospecific transfer of the sulfuryl moiety (-SO 3 ) from 3′-phosphoadenosine 5′-phosphosulfate (PAPS) to the hydroxyls and amines of acceptors (1, 6). Sulfonation often radically alters the interactions of a compound with its target and substantially enhances the target's solubility, transport, and clearance (1, 6, 7). Through these and other mechanisms, SULTs contribute in critical ways to maintaining signaling homeostasis and neutralizing toxins (6,8).Given their wide-ranging roles in regulating cellular processes, it is perhaps expected that SULTs would have evolved means of communicating with their environments-mechanisms that enable them to read and respond to the small-molecule composition of their "milieu." Early screening studies intimated that SULTs might be subject to small-molecule allosteric control (9, 10), and recent work confirms this (11). SULT1A1, the most abundant isoform in adult h...

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Inhibition of Sulfotransferases by Xenobiotics

Cited by 131 publications

References 148 publications

Phase Ii Drug Metabolizing Enzymes

Phase Ii Drug Metabolizing Enzymes

Methamphetamine Regulation of Sulfotransferases in Rat Liver and Brain

The structure of the catechin-binding site of human sulfotransferase 1A1

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