Dehydroepiandrosterone sulfotransferase in the developing human fetus: quantitative biochemical and immunological characterization of the hepatic, renal, and adrenal enzymes.

Barker, Emma; Hume, Robert; Hallas, Anne; Coughtrie, Michael W.H.

doi:10.1210/endo.134.2.8299591

Cited by 84 publications

(45 citation statements)

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“…4 The fetal adrenal gland produces large amounts of DHEA sulfate to support placental estrogen biosynthesis, a requirement reflected in the high level expression of the SULT2A1 isoform in the fetal zone of 2nd and 3rd trimester adrenal. 9,20 Another important example involves the estrogen sulfotransferase (SULT1E1) which displays a particularly high affinity (in the low nM range) for its natural substrate 17b-estradiol, suggesting an important role for this enzyme in modulating estrogen action. 21 Indeed, the enzyme is expressed in the endometrium and is exquisitely regulated during the menstrual cycle 22,23 (probably under the primary influence of progesterone 24,25 ) where it is postulated to moderate estrogenic stimulation of the endometrium around the time of implantation.…”

Section: The Sulfotransferase Superfamily-organisation and Functionmentioning

confidence: 99%

“…13,18,19 The function of certain SULTs in fetal development is fairly well established, such as the production of DHEA sulfate by the adrenal SULT2A1 enzyme. 9 However, the role of others is not so clear. SULT1C enzymes are expressed (in sexually dimorphic manner) in adult rodent liver where they seem to be involved in xenobiotic metabolism-particularly the bioactivation of procarcinogens.…”

Section: The Sulfotransferase Superfamily-organisation and Functionmentioning

confidence: 99%

“…3,4 Rodents have multiple isoforms of the hydroxysteroid SULT subfamily 2A, [5][6][7] whereas so far only a single SULT2A enzyme has been identified and characterised in humans. 8 Also, it is now clear that SULTs are abundantly expressed in the human fetus [9][10][11][12][13] -other 'drug metabolising enzymes' such as the cytochromes P450 (CYPs), UDPglucuronosyltransferases (UGTs) etc are, in general not expressed at significant levels until after birth 14,15 -thus SULTs may represent a front line of chemical defence in the developing human.…”

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confidence: 99%

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Sulfation through the looking glass—recent advances in sulfotransferase research for the curious

2002

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Members of the cytosolic sulfotransferase (SULT) superfamily catalyse the sulfation of a multitude of xenobiotics, hormones and neurotransmitters. Humans have at least 10 functional SULT genes, and a number of recent advances reviewed here have furthered our understanding of SULT function. Analysis of expression patterns has shown that sulfotransferases are highly expressed in the fetus, and SULTs may in fact be a major detoxification enzyme system in the developing human. The X-ray crystal structures of three SULTs have been solved and combined with mutagenesis experiments and molecular modelling, they have provided the first clues as to the factors that govern the unique substrate specificities of some of these enzymes. In the future these and other studies will facilitate prediction of the fate of chemicals metabolised by sulfation. Variation in sulfation capacity may be important in determining an individual's response to xenobiotics, and there has been an explosion in information on sulfotransferase polymorphisms and their functional consequences, including the influence of SULT1A1 genotype on susceptibility to colorectal and breast cancer. Finally, the first gene knockout experiments with SULTs have recently been described, with the generation of estrogen sulfotransferase deficient mice in which reproductive capacity is compromised. Our improved understanding of these enzymes will have significant benefits in such diverse areas as drug design and development, cancer susceptibility, reproduction and development.

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Section: The Sulfotransferase Superfamily-organisation and Functionmentioning

confidence: 99%

Section: The Sulfotransferase Superfamily-organisation and Functionmentioning

confidence: 99%

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confidence: 99%

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Sulfation through the looking glass—recent advances in sulfotransferase research for the curious

2002

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“…Catalytic studies with human foetal liver cytosolic fractions have demonstrated that there is significant sulfotransferase activity toward numerous substances present from mid-gestation (Steiner et al 1982;Pacifici et al 1990;Gilissen et al 1994;Barker et al 1994). From mid-gestation the development of sulfotransferase activity toward 2-naphthol seems to be more advanced than that of UGT with the foetal to adult ratio of sulfotransferase activity far greater than the foetal to adult ratio for UGT activity (Pacifici et al 1990).…”

Section: Sulfation By the Neonatal Human Livermentioning

confidence: 99%

Neonatal Hepatic Drug Elimination

Gow

Ghabrial

Smallwood

et al. 2001

Pharmacology & Toxicology

104

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After the transition from in utero to newborn life, the neonate becomes solely reliant upon its own drug clearance processes to metabolise xenobiotics. Whilst most studies of neonatal hepatic drug elimination have focussed upon in vitro expression and activities of drug-metabolising enzymes, the rapid physiological changes in the early neonatal period of life also need to be considered. There are dramatic changes in neonatal liver blood flow and hepatic oxygenation due to the loss of the umbilical blood supply, the increasing portal vein blood flow, and the gradual closure of the ductus venosus shunt during the first week of life. These changes which may well affect the capacity of neonatal hepatic drug metabolism. The hepatic expression of cytochromes P450 1A2, 2C, 2D6, 2E1 and 3A4 develop at different rates in the postnatal period, whilst 3A7 expression diminishes. Hepatic glucuronidation in the human neonate is relatively immature at birth, which contrasts with the considerably more mature neonatal hepatic sulfation activity. Limited in vivo studies show that the human neonate can significantly metabolise xenobiotics but clearance is considerably less compared with the older infant and adult. The neonatal population included in pharmacological studies is highly heterogeneous with respect to age, body weight, ductus venosus closure and disease processes, making it difficult to interpret data arising from human neonatal studies. Studies in the perfused foetal and neonatal sheep liver have demonstrated how the oxidative and conjugative hepatic elimination of drugs by the intact organ is significantly increased during the first week of life, highlighting that future studies will need to consider the profound physiological changes that may influence neonatal hepatic drug elimination shortly after birth.The development of clinical pharmacology has resulted in a more rational approach to drug therapy, as well as a deeper understanding of the factors capable of influencing drug disposition, and hence drug effects. Of these factors, age is of great importance. However, substantial differences in drug disposition not only exist between neonates and adults, but also among premature neonates, term neonates, infants and children.During the last two decades drug disposition in the neonatal period has been studied extensively. A major impetus for these studies seems to have been a series of incidents involving illness or death following the administration of drugs at ratios of dose/body weight innocuous in an adult (Craft et al. 1974;Gershanik et al. 1982). These studies have shown that the transition from neonate to childhood is characterised by the ontogeny of all of the processes of drug absorption, distribution, hepatic metabolism and renal excretion, with the development of hepatic drug metabolism being particularly important.The extent to which the neonatal drug-metabolising en-

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“…The hSULT2A1 is highly expressed in the adrenal, liver, and intestine, but there is also evidence of its expression in the lung, kidney, and other tissues [28, 29]. …”

Section: Introductionmentioning

confidence: 99%

Binding interactions of hydroxylated polychlorinated biphenyls (OHPCBs) with human hydroxysteroid sulfotransferase hSULT2A1

Ekuase

Lehmler

Robertson

et al. 2014

Chemico-Biological Interactions

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Polychlorinated biphenyls (PCBs) are persistent environmental contaminants, and exposure to PCBs and their hydroxylated metabolites (OHPCBs) has been associated with various adverse health effects. The mammalian cytosolic sulfotransferases (SULTs) catalyze the sulfation of OHPCBs, and the interaction of OHPCBs with both the SULT1 and SULT2 families of these enzymes has received attention both with respect to metabolic disposition of these molecules and the potential mechanisms for their roles in endocrine disruption. We have previously shown that OHPCBs interact with human hydroxysteroid sulfotransferase hSULT2A1, an enzyme that catalyzes the sulfation of dehydroepiandrosterone (DHEA), other alcohol-containing steroids, bile acids, and many xenobiotics. The objective of our current studies is to investigate the mechanism of inhibition of hSULT2A1 by OHPCBs by combining inhibition kinetics with determination of equilibrium binding constants and molecular modeling of potential interactions. Examination of the effects of fifteen OHPCBs on the sulfation of DHEA catalyzed by hSULT2A1 showed predominantly noncompetitive inhibition patterns. This was observed for OHPCBs that were substrates for sulfation reactions catalyzed by the enzyme as well as those that solely inhibited the sulfation of DHEA. Equilibrium binding experiments and molecular modeling studies indicated that the OHPCBs bind at the binding site for DHEA on the enzyme, and that the observed noncompetitive patterns of inhibition are consistent with binding in more than one orientation to more than one enzyme complex. These results have implications for the roles of SULTs in the toxicology of OHPCBs, while also providing molecular probes of the complexity of substrate/inhibitor interactions with hSULT2A1.

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Dehydroepiandrosterone sulfotransferase in the developing human fetus: quantitative biochemical and immunological characterization of the hepatic, renal, and adrenal enzymes.

Cited by 84 publications

References 2 publications

Sulfation through the looking glass—recent advances in sulfotransferase research for the curious

Sulfation through the looking glass—recent advances in sulfotransferase research for the curious

Neonatal Hepatic Drug Elimination

Binding interactions of hydroxylated polychlorinated biphenyls (OHPCBs) with human hydroxysteroid sulfotransferase hSULT2A1

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