Bioactivation of benzylic and allylic alcohols via sulfo-conjugation

Although sulfo-conjugation, in general, has been regarded as a detoxification process in the xenobiotic metabolism, there is a substantial body of data supporting that the same reaction can also lead to activation of certain types of chemical carcinogens and mutagens. Examples include some aromatic amines and amides, alkenylbenzenes, methyl-substituted polyaromatic hydrocarbons, nitrotoluenes and nitrosamines. The N- or O-hydroxy derivatives of these compounds undergo sulfonation to form extremely reactive sulfuric acid esters that can play a role as ultimate carcinogenic/mutagenic metabolites. Previous studies from several laboratories have shown that hydroxymethyl polyarenes, such as hydroxymethylbenz[a]anthracenes, 6-hydroxymethylbenzo[a]pyrene, and 1-hydroxymethylpyrene, are activated to reactive benzylic sulfuric acid esters, preferentially by rat hepatic hydroxysteroid sulfotransferase. Some aromatic hydrocarbons bearing the secondary benzylic hydroxy functionality can also yield electrophilic sulfate esters in the presence of hepatic sulfotransferase activity. Thus, benzylic mono- and dihydroxy derivatives of cyclopenta[cd]pyrene form mutagenic and DNA binding species when incubated with rat liver cytosol and the sulfo-group donor, 3'-phosphoadenosine-5'-phosphosulfate. 1-Hydroxy-3-methylcholanthrene that also possesses the cyclopenta-fused ring system appears to be metabolically activated through sulfo-conjugation. Likewise, benzo[a]pyrene tetraol might be activated through sulfuric acid esterification at one of two benzylic hydroxyl groups. Methylene-bridged polyarenols represent another potential group of cyclic secondary benzylic alcohols that can be activated by sulfotransferases. Certain non-polycyclic aromatic type benzylic alcohols have also been proposed to undergo sulfotransferase-mediated activation. Besides benzylic sulfonation, sulfuric acid esterification of certain allylic alcohols can produce reactive species.