Cell specific activation of benzo[a]pyrene by fibroblasts and hepatocytes

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Abstract
The cell specific activation of benzo[a]pyrene (BP) by embryonic fibroblasts and by mature hepatocytes to intermediates that can interact with DNA, or cause mutations in Chinese hamster V79 cells has been investigated. At BP concentrations of up to 15 ;μM, BP was activated to mutagenic intermediates for the V79 cells by embryonic fibroblasts but not by hepatocytes. However, hepatocytes from rats that had been pretreated with an inducer of the mixed function ox-idases, 3-methylcholanthrene, did metabolize higher doses of BP (> 15 μM) to mutagenic intermediates. BP was extensively metabolized by both cell types, but the hepatocytes and fibroblasts showed differences both in the profiles of BP metabolites and the nature of the BP-DNA adducts formed. Hepatocytes metabolized BP principally to 4,5-dihydro-4,5-dihydroxybenzo[a]pyrene, phenols, and quinones, which underwent further metabolism to water-soluble metabolites. Metabolism of BP to 7,8-dihydro-7,8-dihydroxybenzo[a]-pyrene (BP-7,8-diol) occurred but proceeded rapidly to the formation of triols and tetraols. Fibroblasts metabolized BP predominantly toward the formation of BP-7,8-diol. The proportion of primary metabolites undergoing further metabolism to conjugates was less extensive than in the hepatocytes. Hepatocytes bound more BP to their DNA than the fibroblasts. In the hepatocytes the major DNA adducts formed were hydrophilic derivatives, and no [±]7β,8α-di-hydroxy-9α,10α-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE) adducts were detected even after treatment with BP-7,8-diol. In the fibroblasts, the major BP-DNA adduct was derived from the reaction of BPDE with deoxyguanosine. These results suggest that the differences in the response of embryonic fibroblasts and mature hepatocytes in the activation of BP to a mutagen for mammalian cells is determined at least in part by the overall balance of oxidation and detoxification processes in the cells and, hence, by the levels of critical oxidative intermediates that interact with DNA.