Involvement of P450 1A1 in Benzo(a)Pyrene but Not in Benzo(a)Pyrene‐7,8‐Dihydrodiol Activation by 3‐Methylcholanthrene‐Induced Mouse Liver Microsomes

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Abstract
Synchronous fluorescence spetrophotometry for benzo(a)pyrene‐7,8‐diol‐9,10‐epoxide (BPDE)‐DNA adducts was used to study the activation pathway of benzo(a)pyrene in C57BL/6 mice. Benzo(a)pyrene but not benzo(a)pyrene‐7,8‐diol activation by 3‐methylcholanthrene‐induced mouse liver microsomes was inhibited by a monoclonal antibody (Mab 1–7–1) against CYP1A1/2 suggesting that 1A1 probably takes part in the first P450 reaction. However, aryl hydrocarbon hydroxylase activity, a classical measure of benzo(a)pyrene metabolism, was not inhibited by the same concentration of Mab 1–7–1. None of the other antibodies used, detecting 2A, 2B, 2C or 2E subfamilies, inhibited the adduct formation. Troleandomycin and gestodene, chemical inhibitors of human 3A4, inhibited benzo(a)pyrene‐7,8‐diol activation by 3‐methylcholanthrene‐induced microsomes to some extent only in high concentrations. Although liver microsomes from 3‐methylcholanthrene‐induced mice catalyzed the formation of BPDE‐DNAin vitroclearly more than uninduced microsomes, 3‐methylcholanthrene pretreatmentin vivodecreased the adduct formation in benzo(a)pyrene‐treated mice. These results emphasize the significance of detoxicating and DNA‐repairing pathwaysin vivo.Finally, synchronous fluorescence spectrophotometry for BPDE‐DNA measures the end‐point of the three‐step activation pathway while aryl hydrocarbon hydroxylase measures a one‐step hydroxylation. Thus, these methods should be used rather as corroborative than mutually exclusive assays.

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