Activation of N-hydroxyphenacetin to mutagenic and nucleic acid-binding metabolites by acyltransfer, deacylation, and sulfate conjugation.
N-Hydroxyphenacetin was activated to a mutagen in the Salmonella-Ames test by rabbit liver acyltransferase, rat liver cytosol, and rat liver microsomes. N-[ring]3H]-Hydroxyphenacetin was bound to transfer RNA when activated by acyltransferase from rabbit or rat liver or rat liver microsomes. The acyltransferase-catalyzed binding was not inhibited by paraoxon, a deacetylase inhibitor. The use of N-hydroxyphenacetin radioactively labeled in the acetyl group, as well as the ring, indicated that deacetylation was involved in the microsome-catalyzed binding reaction. In addition, the microsome-catalyzed binding was inhibited 90% by paraoxon. p-Nitrosophenetole, a deacetylated derivative of N-hydroxyphenacetin, was synthesized and bound to transfer RNA without enzymatic activation. Activation of N-hydroxyphenacetin by sulfate conjugation was also found to lead to binding to transfer RNA. The data implicated acyl transfer, deacetylation, and sulfate conjugation as possible routes for the activation of N-hydroxyphenacetin.
D000217:Acyltransferases / Q000378:metabolism*; D000581:Amidohydrolases / Q000378:metabolism*; D000818:Animals; D004789:Enzyme Activation; D008862:Microsomes, Liver / Q000201:enzymology; D009153:Mutagens; D009696:Nucleic Acids / Q000378:metabolism*; D010615:Phenacetin / Q000031:analogs & derivatives* / Q000633:toxicity; D012343:RNA, Transfer / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics; D013431:Sulfates / Q000378:metabolism
D009153:Mutagens; D009696:Nucleic Acids; D013431:Sulfates; C008068:N-hydroxyphenacetin; D012343:RNA, Transfer; D000217:Acyltransferases; D000581:Amidohydrolases; D010615:Phenacetin