Review: Human Sulfotransferases and their role in chemical metabolism

Duke University, Durham, North Carolina, United States
Toxicological Sciences (Impact Factor: 3.85). 04/2006; 90(1):5-22. DOI: 10.1093/toxsci/kfj061
Source: PubMed

ABSTRACT Sulfonation is an important reaction in the metabolism of numerous xenobiotics, drugs, and endogenous compounds. A supergene family of enzymes called sulfotransferases (SULTs) catalyze this reaction. In most cases, the addition of a sulfonate moiety to a compound increases its water solubility and decreases its biological activity. However, many of these enzymes are also capable of bioactivating procarcinogens to reactive electrophiles. In humans three SULT families, SULT1, SULT2, and SULT4, have been identified that contain at least thirteen distinct members. SULTs have a wide tissue distribution and act as a major detoxification enzyme system in adult and the developing human fetus. Nine crystal structures of human cytosolic SULTs have now been determined, and together with site-directed mutagenesis experiments and molecular modeling, we are now beginning to understand the factors that govern distinct but overlapping substrate specificities. These studies have also provided insight into the enzyme kinetics and inhibition characteristics of these enzymes. The regulation of human SULTs remains as one of the least explored areas of research in the field, though there have been some recent advances on the molecular transcription mechanism controlling the individual SULT promoters. Interindividual variation in sulfonation capacity may be important in determining an individual's response to xenobiotics, and recent studies have begun to suggest roles for SULT polymorphism in disease susceptibility. This review aims to provide a summary of our present understanding of the function of human cytosolic sulfotransferases.

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Available from: Ronald G Duggleby, Sep 27, 2015
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    • "Human cytosolic sulfotransferase 2A1 is an important enzyme both for hydroxysteroid hormonal homeostasis and for the metabolism of many drugs and other xenobiotics. Among the physiologic functions of hSULT2A1, the enzyme catalyzes the 3′-phosphoadenosine 5′-phosphosulfate (PAPS)-dependent sulfation of dehydroepiandrosterone (DHEA), other endogenous hydroxysteroids, and many xenobiotic alcohols, phenols, and amines(Duffel 2010; Gamage et al. 2006; James and Ambadapadi 2013; Pacifici and Coughtrie 2005). Such sulfation reactions facilitate the transport, redistribution, and/ or excretion of these molecules. "
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    ABSTRACT: Determining the relationships between the structures of substrates and inhibitors and their interactions with drug-metabolizing enzymes is of prime importance in predicting the toxic potential of new and legacy xenobiotics. Traditionally, quantitative structure activity relationship (QSAR) studies are performed with many distinct compounds. Based on the chemical properties of the tested compounds, complex relationships can be established so that models can be developed to predict toxicity of novel compounds. In this study, the use of fluorinated analogues as supplemental QSAR compounds was investigated. Substituting fluorine induces changes in electronic and steric properties of the substrate without substantially changing the chemical backbone of the substrate. In vitro assays were performed using purified human cytosolic sulfotransferase hSULT2A1 as a model enzyme. A mono-hydroxylated polychlorinated biphenyl (4-OH PCB 14) and its four possible mono-fluoro analogues were used as test compounds. Remarkable similarities were found between this approach and previously published QSAR studies for hSULT2A1. Both studies implicate the importance of dipole moment and dihedral angle as being important to PCB structure in respect to being substrates for hSULT2A1. We conclude that mono-fluorinated analogues of a target substrate can be a useful tool to study the structure activity relationships for enzyme specificity.
    Environmental Science and Pollution Research 07/2015; DOI:10.1007/s11356-015-4886-8 · 2.83 Impact Factor
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    • "In humans, sulfate conjugation of benzene metabolites such as phenol is thought to occur in the liver (McHale et al. 2012). Although humans lack a direct ortholog of Sult3a1, the human sulfotransferase with the closest amino acid similarity is a phenol sulfotransferase called SULT1A1 (Brix et al. 1999; Gamage et al. 2006). Humans contain between one and five copies of SULT1A1 (Gaedigk et al. 2012; Hebbring et al. 2007; Yu et al. 2013) and our results suggest that copy number variation could be associated with the variation in benzene induced toxicity in humans. "
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    ABSTRACT: Background: Inhalation of benzene at levels below the current exposure limit values leads to hematotoxicity in occupationally exposed workers. objective: We sought to evaluate Diversity Outbred (DO) mice as a tool for exposure threshold assessment and to identify genetic factors that infuence benzene-induced genotoxicity. Methods: We exposed male DO mice to benzene (0, 1, 10, or 100 ppm; 75 mice/exposure group) via inhalation for 28 days (6 hr/day for 5 days/week). Te study was repeated using two independent cohorts of 300 animals each. We measured micronuclei frequency in reticulocytes from peripheral blood and bone marrow and applied benchmark concentration modeling to estimate exposure thresholds. We genotyped the mice and performed linkage analysis. Results: We observed a dose-dependent increase in benzene-induced chromosomal damage and estimated a benchmark concentration limit of 0.205 ppm benzene using DO mice. Tis estimate is an order of magnitude below the value estimated using B6C3F1 mice. We identifed a locus on Chr 10 (31.87 Mb) that contained a pair of overexpressed sulfotransferases that were inversely correlated with genotoxicity. Conclusions: The genetically diverse DO mice provided a reproducible response to benzene exposure. Te DO mice display interindividual variation in toxicity response and, as such, may more accurately refect the range of response that is observed in human populations. Studies using DO mice can localize genetic associations with high precision. Te identifcation of sulfotransferases as candidate genes suggests that DO mice may provide additional insight into benzene-induced genotoxicity. © 2015, Public Health Services, US Dept of Health and Human Services .All rights reserved.
    Environmental Health Perspectives 11/2014; 123(3). DOI:10.1289/ehp.1408202 · 7.98 Impact Factor
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    • "Human hydroxysteroid sulfotransferase (hSULT2A1) is a cytosolic enzyme that catalyzes the sulfation of various endogenous and exogenous molecules (Gamage et al., 2006; Duffel, 2010; James and Ambadapadi, 2013). It is highly expressed in the liver and adrenal gland, and present in other tissues as well (Rainey and Nakamura, 2008; Riches et al., 2009). "
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    ABSTRACT: Although tamoxifen is a successful agent for treatment and prevention of estrogen-dependent breast cancer, its use is limited by a low incidence of endometrial cancer. Human hydroxysteroid sulfotransferase 2A1, hSULT2A1, catalyzes the formation of an α-sulfooxy metabolite of tamoxifen that is reactive towards DNA, and this has been implicated in its carcinogenicity. hSULT2A1 also functions in the metabolism of steroid hormones such as dehydroepiandrosterone (DHEA) and pregnenolone (PREG). These roles of hSULT2A1 in steroid hormone metabolism and in generating a reactive metabolite of tamoxifen, have led us to examine its interactions with tamoxifen and several of its major metabolites. We hypothesized that metabolites of tamoxifen may regulate the catalytic activity of hSULT2A1, either through direct inhibition or through serving as alternate substrates for the enzyme. We found that 4-hydroxy-N-desmethyltamoxifen (endoxifen) is a potent inhibitor of hSULT2A1-catalyzed sulfation of PREG and DHEA with Ki values of 3.5 μM and 2.8 μM, respectively. 4-Hydroxytamoxifen (4-OHTAM) and N-desmethyltamoxifen (N-desTAM) exhibited Ki values of 12.7 μM and 9.8 μM, respectively, in the hSULT2A1-catalyzed sulfation of PREG, whereas corresponding Ki values of 19.4 μM and 17.2 μM were observed with DHEA as substrate. A Ki value of 9.1 μM was observed for tamoxifen-N-oxide with DHEA as substrate, and this increased to 16.9 μM for the hSULT2A1-catalyzed sulfation of PREG. Three metabolites were substrates for hSULT2A1, with relative sulfation rates of 4-OHTAM > N-desTAM > endoxifen. These results may be useful in interpreting ongoing clinical trials of endoxifen and in improving the design of related molecules.
    Drug metabolism and disposition: the biological fate of chemicals 08/2014; 42(11). DOI:10.1124/dmd.114.059709 · 3.25 Impact Factor
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