Hepatocyte-mediated mutagenicity of mononitrobenzo[a]pyrenes in Salmonella typhimurium strains.
The mononitro-substituted isomers of benzo[a]pyrene (B[a]P), 1-, 3- and 6-nitrobenzo[a]pyrene (NB[a]P), are environmental pollutants and are metabolized to mutagens in Salmonella by rat-liver homogenate postmitochondrial supernatant (S9) fractions. In this study, activation of these compounds to mutagens was investigated using the hepatocyte-mediated Salmonella mutagenicity assay. Hepatocytes from rats treated with Aroclor 1254 activated both 3-NB[a]P and 1-NB[a]P to mutagens, while 6-NB[a]P was not mutagenic. The positive mutagenicity responses were functions of both the chemical dose and the hepatocyte concentration. By using a nitroreductase-deficient strain (TA98NR) and a transesterificase-deficient strain (TA98/1,8-DNP6), it was verified that the direct-acting mutagenicities of 1- and 3-NB[a]P primarily were due to metabolic processes involving nitroreduction while the S9- and hepatocyte-mediated mutagenicity responses were also dependent on transesterification. When compared with the mutagenic responses produced with S9, the mutations induced by 1- and 3-NB[a]P in the presence of hepatocytes were relatively more dependent upon nitroreductase metabolism and less on transesterification. Thus, intact hepatocytes were capable of activating 1- and 3-NB[a]P to mutagenic metabolites and some of these metabolites appeared to be different from those produced by S9.
D000818:Animals; D001140:Aroclors / Q000494:pharmacology; D001580:Benzopyrenes / Q000378:metabolism / Q000633:toxicity*; D001711:Biotransformation; D008099:Liver / Q000378:metabolism*; D009152:Mutagenicity Tests; D009153:Mutagens / Q000378:metabolism*; D009601:Nitroreductases; D010088:Oxidoreductases / Q000378:metabolism; D051381:Rats; D012486:Salmonella typhimurium / Q000201:enzymology / Q000235:genetics*
D001140:Aroclors; D001580:Benzopyrenes; D009153:Mutagens; C034699:6-nitrobenzo(a)pyrene; C042055:3-nitrobenzo(a)pyrene; C040217:1-nitrobenzo(a)pyrene; D010088:Oxidoreductases; D009601:Nitroreductases