Biol. Pharm. Bull. 29(1) 1—6 (2006)

plasma membrane transporter which extrudes chemotherapeutic agents out of cells, has been associated with the multidrug resistance (MDR) of cancer cells. Numerous studies suggest that the principal physiological role for P-gp is to protect the organism from toxic substances. It is known that this efflux pump is also present in many normal tissues including the epithelium of the gastro-intestinal tract, the renal proximal tubule, the canalicular surface of the hepatocyte, and the endothelial cell surface comprising the blood brain barrier. This ATP-dependent transporter extrudes a wide variety of structurally unrelated compounds, such as vinca alkaloids, etoposides, taxenes and anthracyclines. Compounds such as verapamil, dihydropyridine analogs, quinidine and cyclosporin A reversed this P-gp-mediated multidrug resistance due to their inhibition of transporter activity. In addition to these compounds, it has been revealed that flavonoids and other polyphenols modulate P-gp activity. The important antioxidant activities of polyphenols are well known. Various studies on the structure–activity relationships of their antioxidant activities have been reported. On the other hand, polyphenols, especially flavonoids, are known to modify various physiological functions by interacting with celluar enzymes such as cytochrome P450 and membrane transporters such as glucose transporter. In addition to these activities, it has recently been revealed that polyphenols inhibit the function of ABC transporters such as multidrug resistance associated proteins (MRPs) and breast cancer resistant protein (BCRP), as well as P-gp mentioned above. In this review we analyzed the effects of polyphenols on P-gp function from the standpoints of chemical structure, conformation and hydrophobicity by using multidrug-resistant human epidermal carcinoma cell line KB-C2 cells which overexpress P-gp. Due to the inhibitory activities of polyphenols on P-gp function and their physiological safety, they are candidates for modulators of MDR. To find suitable candidates, it is important to clarify the structure–activity relationships of their inhibitory activities on P-gp function. To reveal the structure–activity relationships is also meaningful because the intake of dietary polyphenols may also alter drug pharmacokinetics and pharmacodynamics via inhibition of P-gp-mediated drug efflux in tissues such as the intestinal epithelium, blood-brain barrier, hepatocytes and renal tubular cells, as well as via inhibition of cytochrome P450.