Relationship of Mammary Tumor Susceptibility, Mammary Cell-Mediated Mutagenesis, and Metabolism of Polycyclic Aromatic Hydrocarbons in Four Types of Rats23

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Abstract
Mammary tumorigenesis by 7,12-dimethylbenz(a)anthracene (DMBA) was tested in two rat stocks and two rat strains: outbred Sprague-Dawley and Long-Evans and inbred Wistar/Furth (WF) and Fischer F344 (F344) rats. Both Sprague-Dawley and WF rats showed comparably high susceptibility to tumorigenesis, whereas Long-Evans and F344 rats proved relatively resistant to tumorigenesis. Cultured mammary stromal and parenchymal cell populations from these four types of rats were used in a cell-mediated mutagenesis assay, and all were found to produce comparable levels of mutagenic metabolites from DMBA. Metabolisms of DMBA and benzo(a)pyrene (BP) were also examined in these cell populations, and similar patterns were found in mammary cells from both susceptible and resistant rat types. The stromal cell populations metabolized both carcinogens at a faster rate than the epithelial cells, but high-pressure liquid chromatographic analysis of ethyl acetate-soluble BP metabolites indicated that both cell types produced similar profiles of BP metabolites in all four rat types. Epithelial cells generally maintained higher intracellular concentrations of carcinogen compared to those of stromal cell populations. The four types were indistinguishable in the amounts and identities of glucuronic acid conjugates of BP that were formed by the mammary cells. The data demonstrate that the rat type-specific susceptibility to polycyclic aromatic hydrocarbon-induced tumorigenesis does not reside in the ability of the mammary cells to metabolically activate these carcinogens.