Our work has presented two lines of evidence suggesting that chemical carcinogen efflux mediated by the multidrug resistant (MDR) glycoprotein 170 (P-gp) may be an important mechanism in diet-dependent cancer prevention. First, we showed that benzo(a)pyrene and 7,12-dimethyl- benzanthracene efflux is mediated by P-gp. Efflux of these carcinogens was markedly higher in MDR cells than in their parent wild-type cells. Additionally, this difference was abrogated by MDR reversal agents, i.e., verapamil and quinine. Second, we showed in MCF-7 breast cancer cells and HCT-15 colon cancer cells that diet-derived flavonols markedly stimulated the P-gp mediated efflux of DMBA and adriamycin, respectively. Flavonols, e.g. galangin, queracetin and kaempferol, are widely distributed in fruits and vegetables and are known to inhibit tumorigenesis. 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 has not been defined. We proposed that P-gp mediated efflux of carcinogens and the modulation of this efflux by dietary factors, e.g. flavonols, may be an important mechanism in cancer prevention. While P-gp expression in cultured cells has been shown to be enhanced by retinoic acid and sodium butyrate, a functional role for diet-derived constituents in modulating the functional role for increased P-gp expression has not been demonstrated. We are currently examining the effects of flavonoids, retinoic acid and other dietary factors on P-gp expression. We propose that P-gp mediated carcinogen efflux is regulated by flavonoids as well as other dietary factors. These nutritional and molecular regulation of P-gp mediated efflux mechanisms are under current investigation.
