ACTIVATION OF N-HYDROXYPHENACETIN TO MUTAGENIC AND NUCLEIC ACID-BINDING METABOLITES BY ACYLTRANSFER, DEACYLATION, AND SULFATE CONJUGATION

Abstract

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 tRNA 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 in the ring indicated that deacetylation was involved in the microsome-catalyzed binding reaction. The microsome-catalyzed binding was inhibited 90% by paraoxon. p-Nitrosophenetole, a deacetylated derivative of N-hydroxyphenacetin, was synthesized and bound to tRNA without enzymatic activation. Activation of N-hydroxyphenacetin by sulfate conjugation led to binding to tRNA. Acyl transfer, deacetylation and sulfate conjugation are possible routes for the activation of N-hydroxyphenacetin.