Human cytosolic sulphotransferases: genetics, characteristics, toxicological aspects

Glatt, Hansruedi; Boeing, Heiner; Engelke, Christina E.H; Ma, Lan; Kuhlow, Andreas; Pabel, Ulrike; Pomplun, Doreen; Teubner, Wera; Meinl, Walter

doi:10.1016/s0027-5107(01)00207-x

Cited by 222 publications

(145 citation statements)

References 84 publications

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“…Acetaminophen, minoxidil as well as dopamine or iodothyronines undergo sulfonation by SULT1A1. SULT1A1 also takes part in transformation of hydroxymethyl polycyclic aromatic hydrocarbons, N-hydroxyderivatives of arylamines, allylic alcohols and heterocyclic amines to their reactive intermediates which are able to bind to nucleophilic structures such as DNA and consequently act as mutagens and carcinogens (Glatt et al, 2001). SULT1A2 also plays an important role in the toxification of several aromatic hydroxylamines (Meinl et al, 2002).…”

Section: Substrates Of Sultsmentioning

confidence: 99%

Phase II Drug Metabolism

Jančová¹,

Siller²

2012

Topics on Drug Metabolism

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Section: Substrates Of Sultsmentioning

confidence: 99%

Phase II Drug Metabolism

Jančová¹,

Siller²

2012

Topics on Drug Metabolism

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“…Sulphotransferase enzymes catalyse sulphation by transferring sulphonate (sulphuryl) group from cofactor 3 0 -phosphoadenosine 5 0 -phosphosulphate to a nucleophilic acceptor substrate to form either a sulphate ester or a sulphamate. These sulphate conjugates are more polar and less reactive than the parent compound and facilitate their excretion (Glatt et al, 2001). However, some sulpho conjugates are strong electrophiles and may covalently bind to DNA and proteins (Glatt et al, 2001).…”

mentioning

confidence: 99%

“…These sulphate conjugates are more polar and less reactive than the parent compound and facilitate their excretion (Glatt et al, 2001). However, some sulpho conjugates are strong electrophiles and may covalently bind to DNA and proteins (Glatt et al, 2001).…”

mentioning

confidence: 99%

Case–control study and meta-analysis of SULT1A1 Arg213His polymorphism for gene, ethnicity and environment interaction for cancer risk

et al. 2008

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Cytosolic sulphotransferase SULT1A1 plays a dual role in the activation of some carcinogens and inactivation of others. A functional polymorphism leading to Arg 213 His substitution (SULT1A1*2) affects its catalytic activity and thermostability. To study the association of SULT1A1*2 polymorphism with tobacco-related cancers (TRCs), a case -control study comprising 132 patients with multiple primary neoplasm (MPN) involving TRC and 198 cancer-free controls was carried out. One hundred and thirteen MPN patients had at least one cancer in upper aerodigestive tract including lung (UADT-MPN). SULT1A1*2 showed significant risk association with UADT-MPN (odds ratio (OR) ¼ 5.50, 95% confidence interval (CI): 1.09, 27.7). Meta-analysis was conducted combining the data with 34 published studies that included 11 962 cancer cases and 14 673 controls in diverse cancers. The SULT1A1*2 revealed contrasting risk association for UADT cancers (OR ¼ 1.62, 95% CI: 1.12, 2.34) and genitourinary cancers (OR ¼ 0.73, 95% CI: 0.58, 0.92). Furthermore, although SULT1A1*2 conferred significant increased risk of breast cancer to Asian women (OR ¼ 1.91, 95% CI: 1.08, 3.40), it did not confer increased risk to Caucasian women (OR ¼ 0.92, 95% CI: 0.71, 1.18). Thus risk for different cancers in distinct ethnic groups could be modulated by interaction between genetic variants and different endogenous and exogenous carcinogens.

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“…To date, five distinct mammalian gene families for cytosolic SULTs (SULTs 1-5) have been identified (7), although SULT3 and SULT5 have not been found in humans (8). The most extensive group of the human cytosolic SULTs is the SULT1 family, which includes SULTs 1A1, 1A2, 1A3, 1B1, 1C1, 1C2, and 1E1.…”

mentioning

confidence: 99%

Structure of a Human Carcinogen-converting Enzyme, SULT1A1

Gamage

Duggleby

Barnett

et al. 2003

Journal of Biological Chemistry

148

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Sulfonation catalyzed by sulfotransferase enzymes plays an important role in chemical defense mechanisms against various xenobiotics but also bioactivates carcinogens. A major human sulfotransferase, SULT1A1, metabolizes and/or bioactivates many endogenous compounds and is implicated in a range of cancers because of its ability to modify diverse promutagen and procarcinogen xenobiotics. The crystal structure of human SULT1A1 reported here is the first sulfotransferase structure complexed with a xenobiotic substrate. An unexpected finding is that the enzyme accommodates not one but two molecules of the xenobiotic model substrate p-nitrophenol in the active site. This result is supported by kinetic data for SULT1A1 that show substrate inhibition for this small xenobiotic. The extended active site of SULT1A1 is consistent with binding of diiodothyronine but cannot easily accommodate ␤-estradiol, although both are known substrates. This observation, together with evidence for a disorder-order transition in SULT1A1, suggests that the active site is flexible and can adapt its architecture to accept diverse hydrophobic substrates with varying sizes, shapes and flexibility. Thus the crystal structure of SULT1A1 provides the molecular basis for substrate inhibition and reveals the first clues as to how the enzyme sulfonates a wide variety of lipophilic compounds.Sulfonation is a widely distributed biological reaction catalyzed by members of the supergene family of enzymes called sulfotransferases (SULTs).1 SULTs utilize the sulfonate donor 3Ј-phosphoadenosine 5Ј-phosphosulfate (PAPS) to catalyze sulfonation, yielding PAP as the desulfonated product of the reaction. These enzymes modify the biological activities of a diverse range of compounds including neurotransmitters, hormones, and drugs. The reaction aids excretion of foreign chemicals but, in some cases, causes bioactivation of carcinogens and mutagens (1-3). SULTs are the focus of intense research in the fields of cancer, drug metabolism, and pharmacogenetics because genetic variation, particularly in isoenzyme SULT1A1, may predispose to lung cancers (4), protect against colorectal cancers (5), and affect the age of onset in breast cancer (6).To date, five distinct mammalian gene families for cytosolic SULTs (SULTs 1-5) have been identified (7), although SULT3 and SULT5 have not been found in humans (8). The most extensive group of the human cytosolic SULTs is the SULT1 family, which includes SULTs 1A1, 1A2, 1A3, 1B1, 1C1, 1C2, and 1E1. Each SULT has distinct substrate preferences but may also exhibit broad and overlapping substrate specificity to span the diversity of chemicals requiring sulfonation. For example, SULT1A3 catalyzes dopamine sulfonation but also accepts p-nitrophenol (pNP) with lower affinity (9, 10). SULT1A1, which shares 93% identity with SULT1A3, also sulfonates dopamine and pNP but with the reverse preference, and in addition it can sulfonate a wide range of hydrophobic molecules (Fig. 1) including xenobiotics and endogenous substrates 3,3Ј-diio...

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Human cytosolic sulphotransferases: genetics, characteristics, toxicological aspects

Cited by 222 publications

References 84 publications

Phase II Drug Metabolism

Phase II Drug Metabolism

Case–control study and meta-analysis of SULT1A1 Arg213His polymorphism for gene, ethnicity and environment interaction for cancer risk

Structure of a Human Carcinogen-converting Enzyme, SULT1A1

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