Inhibition of P-glycoprotein by orange juice components, polymethoxyflavones in adriamycin-resistant human myelogenous leukemia (K562/ADM) cells.
We investigated the effects of the ethyl acetate extract of grapefruit juice (GFJ), that of orange juice (OJ) and their components on the uptake of [(3)H]vincristine into adriamycin-resistant human myelogenous leukemia cells. Its uptake was increased by the extracts of GFJ and OJ up to 7- and 3-fold, respectively, as well as verapamil and cyclosporin A. OJ components, i.e. 3,3',4',5,6,7,8-heptamethoxyflavone, nobiletin and tangeretin, also increased the uptake of [(3)H]vincristine in a concentration-dependent manner. Although GFJ components, dihydroxybergamottin and bergamottin, significantly increased the uptake, their potencies were considerably weaker than those of OJ components. These data suggest that OJ components inhibit P-gp-mediated efflux of [(3)H]vincristine, resulting in the intracellular accumulation of chemotherapeutic drugs. These components may become candidates of multi-drug resistance reversing agents in cancer chemotherapy.
Ikegawa
T
T
Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, 812-8582, Fukuoka, Japan.
Ushigome
F
F
Koyabu
N
N
Morimoto
S
S
Shoyama
Y
Y
Naito
M
M
Tsuruo
T
T
Ohtani
H
H
Sawada
Y
Y
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000085:Acetates; D001628:Beverages; D015153:Blotting, Western; D002957:Citrus / Q000737:chemistry*; D016572:Cyclosporine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D047309:Flavones; D005419:Flavonoids / Q000494:pharmacology*; D011564:Furocoumarins / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D020014:K562 Cells / Q000187:drug effects / Q000378:metabolism; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology; D014316:Tritium; D014700:Verapamil / Q000494:pharmacology; D014750:Vincristine / Q000493:pharmacokinetics
D018435:ATP Binding Cassette Transporter, Subfamily B; D000085:Acetates; D047309:Flavones; D005419:Flavonoids; D011564:Furocoumarins; D010936:Plant Extracts; D014316:Tritium; C059294:3,3',4',5,6,7,8-heptamethoxyflavone; D014750:Vincristine; C007650:ethyl acetate; D004317:Doxorubicin; D016572:Cyclosporine; D014700:Verapamil; C008661:nobiletin; C059006:tangeretin; C068337:bergamottin