Bioactivation of benzylic and allylic alcohols via sulfo-conjugation

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Abstract

Although sulfo-conjugation, in general, has been regarded as a detoxification process in the xenobiotic metabolism, there is a substantial body of data supporting that the same reaction can also lead to activation of certain types of chemical carcinogens and mutagens. Examples include some aromatic amines and amides, alkenylbenzenes, methyl-substituted polyaromatic hydrocarbons, nitrotoluenes and nitrosamines. The N- or O-hydroxy derivatives of these compounds undergo sulfonation to form extremely reactive sulfuric acid esters that can play a role as ultimate carcinogenic/mutagenic metabolites. Previous studies from several laboratories have shown that hydroxymethyl polyarenes, such as hydroxymethylbenz[a]anthracenes, 6-hydroxymethylbenzo[a]pyrene, and 1-hydroxymethylpyrene, are activated to reactive benzylic sulfuric acid esters, preferentially by rat hepatic hydroxysteroid sulfotransferase. Some aromatic hydrocarbons bearing the secondary benzylic hydroxy functionality can also yield electrophilic sulfate esters in the presence of hepatic sulfotransferase activity. Thus, benzylic mono- and dihydroxy derivatives of cyclopenta[cd]pyrene form mutagenic and DNA binding species when incubated with rat liver cytosol and the sulfo-group donor, 3′-phosphoadenosine-5′-phosphosulfate. 1-Hydroxy-3-methylcholanthrene that also possesses the cyclopenta-fused ring system appears to be metabolically activated through sulfo-conjugation. Likewise, benzo[a]pyrene tetraol might be activated through sulfuric acid esterification at one of two benzylic hydroxyl groups. Methylene-bridged polyarenols represent another potential group of cyclic secondary benzylic alcohols that can be activated by sulfotransferases. Certain non-polycyclic aromatic type benzylic alcohols have also been proposed to undergo sulfotransferase-mediated activation. Besides benzylic sulfonation, sulfuric acid esterification of certain allylic alcohols can produce reactive species.

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.

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