SULFOTRANSFERASE-MEDIATED ACTIVATION OF MUTAGENS STUDIED USING HETEROLOGOUS EXPRESSION SYSTEMS

Sulfation is a common final step in the biotransformation of xenobioti cs and is traditionally associated with inactivation. However, the sul fate group is electron-withdrawing and may be cleaved off heterolytica lly in some molecules leading to electrophilic cations which may form adducts with DNA and other important cellular structures. Since endoge nous sulfotransferases do not appear to be expressed in indicator cell s of standard mutagenicity tests, rat and human sulfotransferases have been stably expressed in his(-) Salmonella typhimurium strain TA1538 and Chinese hamster V79 cells. Using these recombinant indicator cells , sulfotransferase-dependent genotoxic activities were detected with N -hydroxy-2-acetylaminofluorene, 2-acetylaminofluorene (in the presence of co-expressed rat cytochrome P450 1A2), hycanthone, 1'-hydroxysafro le, alpha-hydroxytamoxifen and various benzylic alcohols derived from polycyclic aromatic hydrocarbons. In several cases, it was critical th at the reactive sulfuric acid conjugates were formed directly within t he indicator cells, owing to the inefficient penetration of cell membr anes. In other eases, spontaneous benzylic substitution reactions with medium components, such as halogenide ions or amino acids, led to sec ondary, membrane-penetrating reactive species. Different sulfotransfer ases, including related forms from rat and human, substantially differ ed in their substrate specificity towards the investigated promutagens . It is known that some sulfotransferases are expressed with high tiss ue and cell type specificities, This site-dependent expression togethe r with the limitations in the distribution of reactive sulfuric acid c onjugates may explain organotropic effects of compounds activated by t his metabolic pathway. (C) 1998 Elsevier Science Ireland Ltd. All righ ts reserved.