Phenacetin was mutagenic in Salmonella typhimurium TA100 in plate assays when liver fractions from Aroclor-treated hamsters, but not rats, were used. Its known or putative metabolites were synthesized; of these, N-hydroxyphenacetin and N-acetoxyphenacetin were found to be mutagenic in liquid and plate assays, both requiring activation by liver fractions from Aroclor-treated hamsters. 2-Hydroxyphenacetin and 2-acetoxyphenacetin were nonmutagenic. N-Hydroxyphenetidine (the deacetylated metabolite of phenacetin) and p-nitrosophenetole were the only products that were found to be mutagenic per se when assayed under N2 in either Salmonella TA100 and TA100 NR (nitroreductase-deficient) strains.

Phenacetin was administered to male BDVI rats and Syrian golden hamsters, and its urinary metabolites were deconjugated with β-glucuronidase:arylsulfatase. After reactivation by hamster liver fractions, mutagenicity was demonstrated in S. typhimurium TA100 with urine from phenacetin-treated hamsters, but not with that from rats. After treatment with deconjugating enzymes, N-hydroxyphenacetin was isolated from hamster urine by high-performance liquid chromatography and identified by mass spectral analysis. The data support the conclusions that (a) N-hydroxyphenacetin is a proximate mutagenic metabolite of phenacetin which, after N-deacetylation, is responsible for the mutagenicity observed in vitro and in the urine of hamsters and (b) the higher yield of N-hydroxyphenacetin that is formed in the liver of hamsters as compared to rats explains the pronounced species-specific activation of phenacetin into bacterial mutagens.

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These data were presented in part at the 11th Annual Meeting of the European Environmental Mutagen Society, Budapest, Hungary, July 1981. Supported in part by Contract N01-CP-55630 from the National Cancer Institute, NIH, Bethesda, Md.

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