Inhibition of P-glycoprotein function by tannic acid and pentagalloylglucose.
We studied the effects of tannic acid and 1(beta),2,3,4,6-penta-O-galloyl-D-glucose (pentagalloylglucose), one of the components of tannic acid, on the P-glycoprotein (P-gp) function in multidrug-resistant P-gp over-expressing KB-C2 cells. Both tannic acid and pentagalloylglucose markedly elevated the accumulation of P-gp substrates, rhodamine 123 and daunorubicin, by inhibiting their efflux. A 19-fold increase in cellular rhodamine 123 was observed for tannic acid at 60 microM (85 microg mL(-1)) and a 21-fold increase was observed for pentagalloylglucose at 100 microM (94 microg mL(-1)). The increasing effects of these compounds in the accumulation were much larger than that of (-)epigallocatechin-3-O-gallate (EGCG), which has been revealed to have a prominent inhibitory effect on P-gp compared with other flavonoids. Analysis of verapamil-stimulated ATPase activity in membrane vesicles expressing human P-gp suggested that inhibition of P-gp function by tannic acid and pentagalloylglucose was at least partly due to ATPase inhibition of P-gp. The findings also suggested that the presence of a large number of galloyl groups in polyphenols strengthens the interaction with regulatory regions in P-gp.
Kitagawa
Shuji
S
Kobe Pharmaceutical University, Motoyamakita-machi 4-19-1, Kobe 658-8558, Japan. shuji@kobepharma-u.ac.jp
Nabekura
Tomohiro
T
Nakamura
Yutaka
Y
Takahashi
Tomoharu
T
Kashiwada
Yoshiki
Y
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000903:Antibiotics, Antineoplastic / Q000378:metabolism; D003630:Daunorubicin / Q000378:metabolism; D006801:Humans; D047348:Hydrolyzable Tannins / Q000494:pharmacology*; D007624:KB Cells; D020112:Rhodamine 123 / Q000378:metabolism; D013634:Tannins / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D047348:Hydrolyzable Tannins; D013634:Tannins; D020112:Rhodamine 123; C435084:pentagalloylglucose; D003630:Daunorubicin