Sulfation and sulfotransferases 4: bioactivation of mutagens via sulfation.
Sulfation is a common final step in the biotransformation of xenobiotics and is traditionally associated with inactivation. However, the sulfate group is electron-withdrawing and may be cleaved off heterolytically in some molecules, leading to an electrophilic cation. The stable heterologous expression of sulfotransferases in indicator cells of standard mutagenicity tests has substantially improved the accessibility of this activation pathway. Sulfotransferase-mediated genotoxic effects have been demonstrated for numerous benzylic alcohols derived from polycyclic aromatic hydrocarbons and various aromatic hydroxylamines. Also, hycanthone (a benzylic alcohol), alpha-hydroxytamoxifen (an allylic alcohol), 1'-hydroxysafrole (an allylic/benzylic alcohol), and 2-nitropropane are activated to genotoxicants by sulfotransferases. Various reactive sulfate conjugates show strong mutagenic effects only when they are generated directly within the indicator cell, due to their inefficient penetration of cell membranes. In other cases, secondary membrane-penetrating reactive species are formed from sulfuric acid esters by displacement reactions with medium components, such as chloride or amino acids. Reaction with water regenerates the alcohol, which becomes available for a new cycle of activation. Different sulfotransferases from the same species as well as related forms from rat and human differ in their substrate specificities and tissue distributions. These characteristics and reactivities of the sulfate conjugates formed may explain organotropic effects of the compounds activated via sulfotransferases.
Glatt
H
H
German Institute of Human Nutrition, Potsdam-Rehbrücke.
D000818:Animals; D001711:Biotransformation; D002273:Carcinogens / Q000378:metabolism*; D006801:Humans; D009152:Mutagenicity Tests; D009153:Mutagens / Q000378:metabolism*; D051381:Rats; D015238:Sulfotransferases / Q000378:metabolism*; D013463:Sulfuric Acid Esters / Q000378:metabolism
D002273:Carcinogens; D009153:Mutagens; D013463:Sulfuric Acid Esters; D015238:Sulfotransferases