Comparison of benzo(a)pyrene metabolism and sister chromatid exchange induction in mice.
Genetic differences in the inducible arylhydrocarbon hydroxylase (EC 1.14.14.2) (AHH) system, which is involved in the multi-step metabolism of hydrocarbons, are known to exist in both humans and mice. However, the predictive value of AHH activity in human or murine tissues, assayed as benzo(a)pyrene hydroxylation, as an index of individual susceptibility to mutagens and carcinogens, remains unclear because of apparent inconsistencies between results obtained from different in vitro and in vivo systems. This situation may in part reflect the complexity of the pathways involved in drug metabolism, which combine both activation and detoxification. To determine the relationship of metabolic potential to an easily quantified, short-term in vivo end point of genetic damage, we compared the ability of AHH inducible and uninducible mice to metabolize a procarcinogen, benzo(a)pyrene (BP), with the in vivo induction by BP of sister chromatid exchanges (SCEs). SCE induction has been shown to correlate with mutagenesis. We report here that although BP did cause an increase in SCEs in test animals, the extent of this increase did not differ between the inducible C57BL/6 mice and the uninducible DBA/2 mice. Moreover, prior exposure to an AHH inducer, 3-methyl-cholanthrene (3-MC), did not increase the number of BP-induced SCEs in C57BL/6 mice. This lack of correlation between benzo(a)pyrene hydroxylase (BP-OH) inducibility and SCE response reinforces the idea that other metabolic steps, such as detoxification or DNA repair, may influence the overall genetic impact of a drug.
D000818:Animals; D001579:Benzopyrene Hydroxylase / Q000378:metabolism; D001580:Benzopyrenes / Q000378:metabolism* / Q000494:pharmacology; D001853:Bone Marrow / Q000378:metabolism; D003434:Crossing Over, Genetic / Q000187:drug effects*; D004790:Enzyme Induction; D008115:Liver Regeneration; D051379:Mice; D008862:Microsomes, Liver / Q000201:enzymology; D012854:Sister Chromatid Exchange / Q000187:drug effects*
D001580:Benzopyrenes; D001579:Benzopyrene Hydroxylase