This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sabadie, N. Articles by Bartsch, H. Search for Related Content PubMed PubMed Citation Articles by Sabadie, N. Articles by Bartsch, H.

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 Fractions¹

Unit of Chemical Carcinogenesis, International Agency for Research on Cancer, 69372 Lyon Cédex 2, France

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 < 0.1), N-nitrosomorpholine (r = 0.86; p < 0.01), or N-nitroso-N'-methylpiperazine (r = 0.94; p < 0.01). The results are discussed in relation to the possible development of methods for assessing rates of metabolism of environmental carcinogens in human subjects 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-16-carbonitrile, dibenamine, aminoacetonitrile, or disulfiram, but not after treatment with 3-methylcholanthrene, showed a positive correlation with the mutagenicity of the respective 9000 x g liver supernatant fraction mediated in the presence of N-nitrosomorpholine, vinyl chloride, or aflatoxin B₁. These data lend further support that cytochrome P-450-linked monooxygenases in rat liver convert N-nitrosomorpholine, vinyl chloride, and aflatoxin B₁ into mutagenic electrophiles.

¹ Partially supported by Contract NO 1-CP-55630 from the National Cancer Institute, NIH, Bethesda, Md. Some of the data were presented at the International Colloquium of CNRS, No. 256, on "Mécanismes d'altération et de réparation du DNA, relations avec la mutagénèse et la cancérogénese chimique", 4–9 July, 1976, Menton, France, and at the Seventh International Congress of Pharmacology, 1978, Part, France (8).

² Visiting acientist from the Department of Biochemistry (Director: Professor D. Gautheron), University of Lyon, Lyon, France.

³ To whom requests for reprints should be addressed.

Received 7/19/79. Accepted 9/20/79.

This article has been cited by other articles:

				A. Hakura, H. Shimada, M. Nakajima, H. Sui, S. Kitamoto, S. Suzuki, and T. Satoh Salmonella/human S9 mutagenicity test: a collaborative study with 58 compounds Mutagenesis, May 1, 2005; 20(3): 217 - 228. [Abstract] [Full Text] [PDF]

				R.G. Klein, P. Schmezer, R. Hermann, P. Waas, B. Spiegelhalder, and H. Bartsch Strong nasal carcinogenicity and genotoxicity of 1-nitroso-4-methylpiperazine after low dose inhalation in rats Carcinogenesis, August 1, 1999; 20(8): 1629 - 1632. [Abstract] [Full Text] [PDF]