Genetic Differences in Benzo[a]Pyrene-Initiated Tumorigenesis in Mouse Skin

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Abstract
C57BL/6, BALB/c, and C3Hf/He are three highly inbred mouse strains that are all genetically ‘responsive’ with regard to the Ah locus but exhibit important differences in sensitivity to epidermal carcinoma when benzo[a]pyrene is applied topically three times weekly. Skin microsomes from the most sensitive strain C57BL/6 display the most inducible metabolism of benzo[a]pyrene (especially in the benzylic ring adjacent to the ‘bay region’), the intermediate strain BALB/c demonstrates intermediate levels of metabolism, and the least sensitive strain C3Hf/He shows the least inducible metabolism of benzo[a]pyrene. Genetic differences in DNA binding of benzo[a]pyrene metabolites generated by skin microsomes in vitro from these three strains, on the other hand, are not correlated with genetic differences in sensitivity to epidermal benzo[a]pyrene-induced cancer. DNA is shown to be an infinite target: When liver microsomes from C57BL/6, C3Hf/He, or DBA/2 are each incubated in vitro with fetal DNA derived from C57BL/6, C3Hf/He, or DBA/2, the binding profile (ratios of peaks representing benzo[a]pyrene nucleoside adducts) is independent of the source of DNA and totally dependent upon the source of microsomes.