In the present study we have investigated the formation of DNA adducts by dimethylbenzanthracene, a polycyclic aromatic hydrocarbon (PAH), in normal and drug-resistant MCF-7 human breast cancer cell lines. We hope that this model system will provide insights into the mechanism of carcinogenesis by xenobiotics. We have also used this system to screen for effectors of this process, such as dietary compounds. 7,12-dimethylbenzanthracene (DMBA), is a mammary carcinogen that is metabolized in cells by cytochrome P450, forming activated compounds which bind specific residues of DNA and initiate carcinogenesis. Adduct formation in wild-type (WT) MCF-7 cells exposed to [3H]-DMBA increased in a dose-and time-dependent fashion, but was greatly reduced in adriamycin-resistant (AR) or benzo(a)pyrene-resistant (BRP) MCF-7 cells. The drug-resistant cell lines also exhibited less cytotoxicity when grown in the presence of DMBA. Since such a reduction in cytotoxicity and adduct formation could be the result of changes in DMBA metabolism, we assayed the activity of cytochrome P450 1a (CYP1a), the first enzyme in the metabolic pathway of DMBA, CYP1A activity was not detectable in the cell lines tested, however, there was a rapid induction of activity in WT cells exposed to DMBA or other PAHs. This induction was reduced in AR cells compared to WT and was absent in BPR cells. These results indicate that a change in DMBA metabolism is responsible for the decreased adduct formation seen in the resistant cell lines. Such insights into the mechanism of carcinogen activation may have important implications for the study of carcinogenesis caused by important enviornmental polycyclic aromatic hydrocarbons.
