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Chem Biol Interact. 2000 Dec 1;129(1-2):141-70.

Sulfotransferases in the bioactivation of xenobiotics.

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1
Department of Toxicology, Deutsches Institut für Ernährungsforschung (DIfE), Arthur-Scheunert-Allee 114-116, D-14558, Potsdam-Rehbrücke, Germany. glatt@www.dife.de

Abstract

Conjugation of xenobiotics is often associated with detoxification. However, this traditional view is one-sided. In particular, numerous compounds are known that are metabolized to chemically reactive metabolites via sulfation (O-sulfonation). This can be rationalized by the fact that the sulfate group is electron-withdrawing and may be cleaved off heterolytically in appropriate molecules, thus leading to the formation of a strongly electrophilic cation. The heterologous expression of sulfotransferases in indicator cells of standard mutagenicity tests has substantially improved the accessibility of this activation pathway. The use of this technology is important, since many reactive sulfate conjugates only show strong toxicological effects if they are generated directly within the indicator cell, due to their insufficient penetration of cell membranes. Xenobiotic-metabolizing sulfotransferases are cytosolic enzymes, which form a superfamily (SULT). Eleven distinct human SULT forms are known, which strongly differ in their tissue distribution and their substrate specificity. Common functionally relevant genetic polymorphisms of the transcribed region are known for two of the forms, SULT1A1 and 1A2. Studies using recombinant test systems demonstrate that many promutagens are activated with high selectivity by an individual SULT form. Pronounced differences in promutagen activation were detected between the different human forms, including their allelic variants, and also between orthologous SULTs from different species. Therefore, SULTs may be involved in the individual genetic disposition, species differences, and organotropisms for toxicological effects of chemicals. Activation by SULTs differs from other activation pathway in its cyclic nature: reaction of a sulfuric acid ester with water usually regenerates the hydroxylated compound, which becomes available for a new cycle of activation. SULT-mediated reactivation may even occur if another initial reactive species, e.g. an epoxide, has reacted with water.

PMID:
11154739
[Indexed for MEDLINE]
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