Microsomal activation of 1- and 3-nitrobenzo[a]pyrene to mutagens in Chinese hamster ovary cells

• Published in: Mutagenesis Vol. 3; no. 3; p. 233
• Main Authors: Thornton-Manning, J R, Chou, M W, Fu, P P, Heflich, R H
• Format: Journal Article
• Language: English
• Published: England 01.05.1988
• Subjects: Animals; Benzopyrenes - pharmacokinetics; Benzopyrenes - toxicity; Biotransformation; Cells, Cultured; Cricetinae; Epoxide Hydrolases - antagonists & inhibitors; Liver; Microsomes - metabolism; Mutagenicity Tests; Mutagens - pharmacokinetics; Subcellular Fractions; Trichloroepoxypropane - pharmacology
• ISSN: 0267-8357; 1464-3804
• DOI: 10.1093/mutage/3.3.233

1- and 3-nitrobenzo[a]pyrene (1- and 3-nitro-BaP) are environmental pollutants and are S9-mediated mutagens in the Chinese hamster ovary (CHO) cell/hypoxanthine-guanine phosphoribosyl transferase assay. In this study, we examined the pathways leading to the mutagenic activation of these compounds in CHO cells. The microsomal metabolites of 1- and 3-nitro-BaP, the 1- and 3-nitro-BaP trans-7,8-dihydroxy-7,8-dihydrodiols (trans-7,8-dihydrodiols) and the 1- and 3-nitro-BaP trans-9,10-dihydrodiols, were isolated and tested for mutagenicity. At the concentrations assayed, both trans-9,10-dihydrodiols were non-mutagenic with and without S9 activation. In contrast, the trans-7,8-dihydrodiols of 1- and 3-nitro-BaP were direct-acting mutagens and these responses were similar in magnitude to the S9-mediated mutagenicities of the parent nitro-BaPs. S9 increased the mutagenic responses of the trans-7,8-dihydrodiols approximately 20-fold. Inhibition of epoxide hydrolase decreased the S9-mediated mutagenicity of 1-nitro-BaP by half, but doubled the S9-mediated mutagenicity of 3-nitro-BaP. These results suggest that in CHO cells: (i) the major route of mutagenic activation of 1- and 3-nitro-BaP involves S9-generated derivatives of the trans-7,8-dihydrodiols, e.g. bay-region diol epoxides; (ii) reactive nitroarene oxides may contribute to mutation induction by 3-nitro-BaP; and (iii) metabolic routes involving trans-9,10-dihydrodiol formation result in detoxification.