The efflux mechanism of chemical carcinogens has not been well defined. Two lines of evidence suggested that chemical carcinogen efflux may be mediated by a transmembrane pump or the multidrug resistant (MDR) glycoprotein 170 (P-gp). We showed that benzo(a)pyrene efflux was increased in human breast cancer adriamycin-resistant cells expressing high levels of P-gp. The overexpression of P-gp in rat liver nodules induced by the chemical carcinogen tetrachloro-dibenzo-p-dioxin (TCDD) has been reported by others. Although P-gp, a product of the mdr gene, is known to play a critical role in cellular resistance to cytotoxic drugs, its function in normal cells is not well understood. We proposed that P-gp mediated efflux of carcinogens and the modulation of this efflux by hormones and dietary factors may be an important mechanism in cancer prevention. We demonstrated that in our series of adriamycin-- resistant MCF-7 cells in which expression of the mdr gene, levels of membrane P-gp, and rates of adriamycin efflux are correlated with the efflux of benzo(a)pyrene and 9, 10-dimethy-1, 2-benzanthracene. These findings suggest that the efflux of certain carcinogens can be mediated by P-gp and support our hypothesis that P-gp may play a role in protecting normal cells from chemical carcinogens. While P-gp expression in cultured cells has been shown to be enhanced by retinoic acid and sodium butyrate, the role of diet-derived constituents in modulating P-gp expression or function remains unclear. We tested a series of flavonoid compounds for their effects on adriamycin accumulation in human colon cells and adriamycin-resistant MCF7 human breast cells. We found a number of flavonoids markedly decreased the accumulation of ADR. Several flavonoids also inhibited specific binding to P-gp in crude membrane preparations as measured by 3H-azidopine photoaffinity labeling. We conclude that flavonoids can exert significant acute effects on cellular drug accumulation through direct interaction with P-gp. We are extending our studies of the flavonoid effect on carcinogen efflux to normal tissues. We propose that P-gp mediated carcinogen efflux may be regulated by dietary factors in normal tissues. These biochemical and molecular mechanisms are under current investigation.
