Cytosolic sulfotransferases (SULT) catalyze the sulfation of structurally diverse drugs, endogenous compounds and xenobiotics. These reactions involve the transfer of a sulfuryl group from 3-phosphoadenosine 5-phosphosulfate (PAPS) to the hydroxyl/amino groups of acceptor molecules. Although sulfate conjugation is generally considered as a detoxication pathway producing more water-soluble and often less toxic metabolites, sulfation of certain classes of compounds produce sufficiently electrophilic metabolites that can covalently bind to cellular macromolecules, DNA and RNA. The important roles of electrophilic sulfate ester metabolites in the metabolic activation, mutagenicity and ultimate carcinogenicity of many xenobiotics have been considerably elucidated. Examples include the class of hydroxymethyl polycyclic aromatic hydrocarbons, allylic alcohols, N-hydroxy derivatives of carcinogenic arylamines and heterocyclic amines. Results obtained by many scientists during the last two decade correlate with a hypothesis that electrophilic sulfate esters may be the major ultimate carcinogenic forms of many, if not most, procarcinogens derived from benzylic/allylic alcohols and hydroxy arylamines. Careful analysis of these results suggest that the activities of human hydroxysteroid sulfotransferase (hHST), and a related form in rat liver, rat hydroxysteroid sulfotransferase a (STa), as well as aryl sulfotransferases both from rat and human liver, account for a substantial portion of the activation of benzylic/allylic alcohols in these species. Moreover, aryl sulfotransferases have also been indicated as the responsible SULT family in the bioactivation of hydroxy arylamines in the liver of different species including human. Molecular cloning of the individual sulfotransferases and expression of these individual forms in heterologous expression systems have allowed us to better understand the role of SULTs in the bioactivation of different procarcinogens and the form of sulfotransferase involved in their bioactivation. Additional structure-activity studies with homogeneous forms of rat liver STa and AST IV have also yielded comparative insight into some of the parameters important in recognition of substrates and inhibitors by these enzymes.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, 06330 Hipodrom, Ankara; Turkey.