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


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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    • "Positive and negative control samples for each family of enzymes were incubated in parallel under the same conditions described above. In the positive control samples for UGT and SULT activity, 4-nitrophenol (10 M, final concentration) was selected as the substrate and the formation of 4-nitrophenolglucuronide and 4-nitrophenolsulfate, respectively, was monitored [14] [15]. No positive control samples for CYP activity were prepared, because data about the catalytic activity of major human liver CYPs was provided by the HLM vendor. "
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    ABSTRACT: Ethylphenidate is a new potent synthetic psychoactive drug, structurally related to methylphenidate. Using human liver microsomes and cytosol, we have investigated for the first time the Phase-I and Phase-II in vitro metabolism of ethylphenidate. The structure of the metabolites was elucidated by hybrid quadrupole time-of-flight mass spectrometry. Overall, seven Phase-I, but no Phase-II metabolites were detected. Ethylphenidate underwent hydroxylation forming two primary mono-hydroxylated metabolites and, subsequently, dehydration and ring opening with an additional hydroxylation, forming secondary metabolites. The involvement of different human cytochrome P450 (CYP) enzymes in the formation of ethylphenidate metabolites was investigated using a panel of human recombinant CYPs (rCYPs). rCYP2C19 was the most active recombinant enzyme involved in the formation of all seven ethylphenidate metabolites detected, although other rCYPs (rCYP1A2, rCYP2B6, rCYPC9, rCYP2D6, and rCYP3A4, but not rCYP2E1) played a role in the metabolism of ethylphenidate. All metabolites identified in the present study can be considered as potential specific biomarkers of ethylphenidate in toxicological studies. Additionally, ritalinic acid and methylphenidate were formed by non-enzymatic hydrolysis and trans-esterification, and, therefore, they cannot be considered as (oxidative) metabolites of ethylphenidate. The presence of methylphenidate and ritalinic acid cannot be exclusively associated to the use of ethylphenidate, since methylphenidate is a drug itself and ritanilic acid can be formed from both ethylphenidate and methylphenidate.
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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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    • "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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