Current Status of the Cytosolic Sulfotransferases in the Metabolic Activation of Promutagens and Procarcinogens

Abstract

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.

Natural polyphenol disposition via coupled metabolic pathways

“…Phase I enzymes consist primarily of the cytochrome P450 (CYP) superfamily of microsomal enzymes [1]. Phase II metabolizing or conjugating enzymes consist of many superfamilies of enzymes mainly including sulfotransferases (SULT) [3], UDPglucuronosyltransferases (UGT) [4], and glutathione transferases [5]. Efflux transporters, including p-glycoprotein (p-gp) [6], multidrug resistance associated proteins (MRPs) [6], and organic anion transporter (OAT) [7] are expressed in many tissues such as the liver, intestine, kidney and brain, where they present a formidable barrier to drug penetration, and play crucial roles in drug absorption, distribution and excretion [6,8,9].…”

The Structure of Human SULT1A1 Crystallized with Estradiol

“…SULTs utilize the cofactor 3Ј-phosphoadenosine 5Ј-phosphosulfate (PAPS) as the sulfonate (SO 3 Ϫ1 ) donor in such reactions that generally lead to the detoxification of substrates by making them more water-soluble and thereby readily excretable via the kidneys. However, in the case of mutagenic and carcinogenic N-hydroxyarylamines and heterocyclic amines and benzylic alcohols of polycyclic aromatic hydrocarbons, sulfonation is a critical step in their metabolic activation to electrophiles that can bind tissue macromolecules such as DNA (3)(4)(5)(6). Further, sulfonation has been shown to activate the antihypertensive and hair growth stimulant minoxidil (7).…”

E. coli nitroreductase/CB1954 gene-directed enzyme prodrug therapy: role of arylamine N-acetlytransferase 2

“…16 The highly unstable esters decompose to electrophilic nitrinium ions that alkylate cellular macromolecules and other nucleophiles. To test whether any of the major human sulfotransferases can activate CB1954 metabolites, stably transfected SKOV3-NTR cells expressing various SULT genes (SULT1A1, 1A2, 1A3, 1E1 and 2A1) were generated.…”