Comparison of the hydroxylation of benzo(a)pyrene with the metabolism of vinyl chloride, N-nitrosomorpholine, and N-nitroso-N'-methylpiperazine to mutagens by human and rat liver microsomal fractions.

Abstract

Abstract Carcinogen metabolism in vitro was studied in 20 surgical liver specimens from adult male and female human subjects. A 60-fold interindividual variation in aryl hydrocarbon [benzo-( a )pyrene] hydroxylase activity was seen; the capacity to convert vinyl chloride, N -nitroso- N ′-methylpiperazine, and N -nitrosomorpholine into electrophiles mutagenic to Salmonella typhimurium varied 9-, 17-, and 35-fold, respectively. The mean enzymic capacity relative to that of liver from untreated rats was 84% for vinyl chloride, 42% for N -nitrosomorpholine, and 380% for N -nitroso- N ′-methylpiperazine. When aryl hydrocarbon [benzo( a )pyrene] hydroxylase activity in human liver specimens was plotted against mutagenicity in S. typhimurium mediated by liver microsomes from the same specimens, a positive correlation was obtained in the presence of vinyl chloride ( r = 0.55; p N -nitrosomorpholine ( r = 0.86; p N -nitroso- N ′-methylpiperazine ( r = 0.94; p in vivo using nontoxic drugs that are metabolized by the same enzymes that metabolize carcinogens. Hepatic aryl hydrocarbon [benzo( a )pyrene] hydroxylase activity following treatment of rats with phenobarbitone, pregnenolone-16α-carbonitrile, dibenamine, aminoacetonitrile, or disulfiram, but not after treatment with 3-methylcholanthrene, showed a positive correlation with the mutagenicity of the respective 9000 × g liver supernatant fraction mediated in the presence of N -nitrosomorpholine, vinyl chloride, or aflatoxin B 1 . These data lend further support that cytochrome P-450-linked monooxygenases in rat liver convert N -nitrosomorpholine, vinyl chloride, and aflatoxin B 1 into mutagenic electrophiles.