Bioactivation of benzylic and allylic alcohols via sulfo-conjugation
Introduction
Sulfo-conjugation (or sulfonation), in general, plays an important role in the detoxification of a wide array of xenobiotics or their primary metabolites. Different isoforms of the sulfotransferase superfamily catalyze transfer of the sulfuryl moiety from the co-substrate, 3′-phosphoadenosine-5′-phosphosulfate (PAPS), to specific types of acceptor molecules including phenols, alcohols and (hydroxyl)amines. Sulfonation usually renders relatively lipophilic xenobiotics more polar and excretable products. However, there has been accumulated evidence supporting that sulfonation can lead to activation for certain classes of chemical carcinogens and mutagens 1, 2. This review examines the sulfotransferase-mediated bioactivation of some benzylic and allylic alcohols.
Section snippets
Hydroxymethyl PAHs
Benzylic esters bearing a good leaving group such as sulfate, phosphate or acetate have been proposed to play a role as ultimate electrophilic and carcinogenic metabolites of some (hydroxy)methyl PAHs 3, 4. In an attempt to elucidate the metabolic formation of reactive benzylic esters, Flesher and his colleagues 5, 6initially determined the sulfotransferase-mediated covalent binding of 7-hydroxymethyl-12-methylbenz[a]anthracene and 6-hydroxymethylbenzo[a]pyrene to exogenous DNA in the presence
Hycanthone
Hycanthone is a schistosomicidal agent ([39]; structure shown in Fig. 4). It is no longer used for therapeutic purposes because of its adverse effects including mutagenicity and carcinogenicity 40, 41. It was hypothesized that hycanthone is enzymatically esterified in the target cell to a reactive ester bearing a good leaving group (e.g., sulfate), that dissociates non-enzymatically to yield DNA alkylating species 42, 43. In support of this hypothesis, a model ester hycanthone N-methylcarbamate
Sulfotransferase-mediated activation of allylic alcohols
Various allylic compounds have been reported to exert mutagenicity 49, 50. The esters of allyl alcohol have been suggested to form transient carbonium ion capable of reacting with nucleophiles. Thus, a strong correlation between alkylating activity of allyl halides and their mutagenic potency has been reported [50]. Furthermore, allylmercapturic acid was detected in the urine of rats after subcutaneous injection of allyl sulfate [51]. However, neither biological formation of allyl sulfate and
Acknowledgements
This work was supported by the Korea Science and Engineering Foundation through the Research Center for New Drug Development (RCNDD-KOSEF) at the Seoul National University.
References (71)
Sulfonation in chemical carcinogenesis
Chem.-Biol. Interact.
(1994)- et al.
Binding of 6-hydroxymethylbenzo[a]pyrene and 6-acetoxymethylbenzo[a]pyrene to DNA
Chem.-Biol. Interact.
(1979) - et al.
A hydroxymethyl sulphate ester as an active metabolite of the carcinogen, 5-hydroxymethylchrysene
Biochem. Pharmacol.
(1986) - et al.
Inhibition of the mutagenicity and metabolism of 6-methylbenzo[a]pyrene and 6-hydroxymethylbenzo[a]pyrene
Biochem. Pharmacol.
(1986) - et al.
The strong hepatocarcinogenicity of the elctrophilic and mutagenic metabolite 6-sulfooxymethylbenzo[a]pyrene and its formation of benzylic DNA adducts in the livers of infant male B6C3F1 mice
Biochem. Biophys. Res. Commun.
(1990) - et al.
Hepatic DNA and RNA adduct formation from 7-hydroxymethyl-12-methylbenz[a]anthracene and its electrophilic sulfuric acid ester metabolite in preweanling rats and mice
Biochem. Biophys. Res. Commun.
(1987) - et al.
Age- and sex-related differences in activation of the carcinogen 7-hydroxymethyl-12-methylbenz[a]anthracene to an electyrophilic sulfuric acid ester metabolite in rats: possible involvement of hydroxysteroid sulfotransferase activity
Biochem. Pharmacol.
(1991) - et al.
Cloning and sequencing of a rat liver cDNA encoding hydroxysteroid sulfotransferase
Biochem. Biophys. Res. Commun.
(1989) - et al.
Activation of benzylic alcohols to mutagens by rat and human sulfotransferases expressed in Escherichia coli
Eur. J. Pharmacol.
(1995) - et al.
Activation of promutagens by endogenous and heterologous sulfotransferases expressed in continuous cell cultures
Toxicol. Lett.
(1994)