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Interspecies Differences in the Major DNA Adducts Formed from Benzo(a)pyrene but not 7,12-Dimethylbenz(a)anthracene in Rat and Human Mammary Cell Cultures¹

University of Wisconsin-Madison, Department of Human Oncology, K4/310, University of Wisconsin Clinical Cancer Center, Madison, Wisconsin 53792 [C. J. M., M. N. G.]; and Purdue University, Department of Medicinal Chemistry and Pharmacognosy, School of Pharmacy and Pharmacal Sciences, West Lafayette, Indiana 47907 [D. P. S., R. J. M., W. M. B.]

Mammary epithelial cells from rats and humans show both quantitative and qualitative species- and carcinogen-specific differences in their abilities to activate benzo(a)pyrene (B(a)P) and 7,12-dimethyl-benz(a)anthracene (DMBA). Previous studies of the DNA binding of these compounds in mammary epithelial cells demonstrated that rat cells bound relatively more DMBA than B(a)P to DNA under identical treatment conditions, while the opposite pattern was exhibited by human mammary epithelial cells. The specific DNA adducts formed in these cells after 24-h incubations with [³H]DMBA and [³H]B(a)P were analyzed to determine if there were qualitative as well as quantitative differences in the amounts of individual adducts. Similar proportions of specific DMBA-DNA adducts were found in both rat and human cells, although the total amount of adducts formed was significantly higher in the rat cells. In contrast, an essentially qualitative species-specific difference was observed in the major B(a)P-DNA adduct present in the rat and human cells. The major B(a)P adduct formed in the human mammary epithelial cells was identified as the (+)-anti-B(a)P-7,8-dihydrodiol-9,10-epoxide(BPDE)-deoxyguanosine adduct. However, this adduct was formed at very low levels in the rat mammary epithelial cells. The rat cells contained a large proportion of syn-BPDE adducts, and other unidentified B(a)P-DNA adducts. The high level of the (+)-anti-BPDE-deoxyguanosine adduct in the human but not the rat mammary cells is consistent with the potential role of (+)-anti-BPDE in the high mutagenic activity of B(a)P in the cell-mediated mutagenesis assays using the human mammary cells as activators, and the low mutagenic activity of B(a)P when rat cells were used as activators. The quantitative differences in the activation of DMBA by cells from these two species are also consistent with the cell-mediated mutagenic activities of DMBA using these cells as activators. These results suggest that the higher carcinogenic activity of DMBA compared to B(a)P in the rat mammary gland may not be indicative of the relative carcinogenic potencies of these compounds for human mammary cells.

¹ This investigation was supported by Grants CA30295, CA28954, and CA40228 from the National Cancer Institute, Department of Health and Human Services.

² To whom requests for reprints should be addressed, at Department of Human Oncology, University of Wisconsin-Madison, Clinical Cancer Center, K4/310 CSC, 600 Highland Avenue, Madison, WI 53792.

³ Present address: Department of Chemistry, Wayne State University, Detroit, MI 48202.

Received 1/21/87. Revised 5/ 7/87. Accepted 5/19/87.