The mechanism by which oncogenes are activated by environmental and dietary carcinogens in human cancers remains unclear. For chemical carcinogens, the emphasis has been on activation and detoxification mechanism. We propose another cellular protection mechanism against chemical carcinogens: carcinogen resistance through increased efflux. An attractive possibility is that the pleotropic drug efflux pump mediated by a plasma membrane glycoprotein serves to protect normal tissues against carcinogenic insult. The multidrug resistant gene (MDR) codes for a 170 KDa plasma membrane glycoprotein (p-gp), originally described by Ling et al., which functions as an energy-dependent chemotherapeutic drug efflux pump in cancer cells. We propose that it may also work as an efflux pump for chemical carcinogens. Using human breast cancer MCF-7 cells with different stages of adriamycin resistance and corresponding p-gp levels to test our hypothesis, we found that chemical carcinogen, benzo(a)pyrene, may share the mechanism for drug efflux in these cells derived by continuous exposure to adriamycin. We are studying the role of the p-gp as an efflux pump for other dietary carcinogens. Its regulation by nutrients may be the first step in cancer prevention.
