Mutagenesis and DNA binding of benzo(a)pyrene in cocultures of rat hepatocytes and human fibroblasts.
The genotoxicity of benzo(a)pyrene (BP) was investigated in combined cultures of rat hepatocytes and human diploid fibroblasts. Freshly isolated rat hepatocytes were shown to activate BP to a species which bound to and damaged hepatocyte and fibroblast DNA. A significant increase in the hypoxanthine-guanine phosphoribosyltransferase mutation frequency was induced when 10 to 100 microM BP was added to the cocultures. A comparative analysis of the binding of BP metabolites to hepatocyte and fibroblast DNA revealed that approximately 4 times more [3H]BP metabolites were bound to the fibroblast DNA than were bound to the hepatocyte DNA (per microgram DNA). Activation of BP by the fibroblasts themselves was shown not to be the cause of the relatively greater binding of BP to fibroblast DNA than to the hepatocyte DNA. These results suggest that proximate and/or ultimately carcinogenic metabolites of BP are readily released from isolated hepatocytes and that the metabolites are sufficiently stable and long lived so as to bind to the DNA of an adjacent cell. The relative protection of the hepatocytic DNA from BP metabolites that generated in the cytoplasm of the hepatocyte may be significant in view of the observations that the liver is not under normal conditions a target of BP carcinogenicity in vivo.
D000818:Animals; D001564:Benzo(a)pyrene; D001580:Benzopyrenes / Q000494:pharmacology*; D004247:DNA / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009153:Mutagens / Q000494:pharmacology*; D009154:Mutation; D051381:Rats
D001580:Benzopyrenes; D009153:Mutagens; D001564:Benzo(a)pyrene; D004247:DNA