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

The cell specific activation of benzo[a]pyrene (BP) by embryonicfibroblasts and by mature hepatocytes to intermediates thatcan interact with DNA, or cause mutations in Chinese hamsterV79 cells has been investigated. At BP concentrations of upto 15 ;µM, BP was activated to mutagenic intermediatesfor the V79 cells by embryonic fibroblasts but not by hepatocytes.However, hepatocytes from rats that had been pretreated withan inducer of the mixed function ox-idases, 3-methylcholanthrene,did metabolize higher doses of BP (> 15 µM) to mutagenicintermediates. BP was extensively metabolized by both cell types,but the hepatocytes and fibroblasts showed differences bothin the profiles of BP metabolites and the nature of the BP-DNAadducts formed. Hepatocytes metabolized BP principally to 4,5-dihydro-4,5-dihydroxybenzo[a]pyrene,phenols, and quinones, which underwent further metabolism towater-soluble metabolites. Metabolism of BP to 7,8-dihydro-7,8-dihydroxybenzo[a]-pyrene(BP-7,8-diol) occurred but proceeded rapidly to the formationof triols and tetraols. Fibroblasts metabolized BP predominantlytoward the formation of BP-7,8-diol. The proportion of primarymetabolites undergoing further metabolism to conjugates wasless extensive than in the hepatocytes. Hepatocytes bound moreBP to their DNA than the fibroblasts. In the hepatocytes themajor DNA adducts formed were hydrophilic derivatives, and no[±]7ß,8-di-hydroxy-9,10-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 fromthe reaction of BPDE with deoxyguanosine. These results suggestthat the differences in the response of embryonic fibroblastsand mature hepatocytes in the activation of BP to a mutagenfor mammalian cells is determined at least in part by the overallbalance of oxidation and detoxification processes in the cellsand, hence, by the levels of critical oxidative intermediatesthat interact with DNA.