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Vol. 293, Issue 1, 230-236, April 2000

Polymethoxylated Flavones in Orange Juice Are Inhibitors of P-glycoprotein but Not Cytochrome P450 3A41

Hitomi Takanaga, Ayako Ohnishi, Shiho Yamada, Hirotami Matsuo, Satoshi Morimoto, Yukihiro Shoyama, Hisakazu Ohtani and Yasufumi Sawada

Department of Pharmaceutics (H.T., A.O., S.Y., H.M., H.O., Ya.S.) and Pharmacognosy (S.M., Yu.S.), Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan

The presence in orange juice of compounds that specifically inhibit the P-glycoprotein (P-gp) drug efflux transporter, but not the cytochrome P450 (CYP) isozyme CYP3A4, was investigated. The uptake of [3H]vinblastine, a substrate of P-gp, by Caco-2 cells was measured. An ethyl acetate extract of orange juice did not affect the initial uptake rate of [3H]vinblastine but significantly increased the steady-state uptake, as did cyclosporin A (20 µM), an inhibitor of P-gp. No significant effect on the uptake of 3-O-[3H]methylglucose or [14C]phenylalanine by Caco-2 cells was found, compared with the control. When the extract was separated on a Cosmosil column, the eluate with 70% methanol showed the most potent ability to increase [3H]vinblastine uptake. Additional separation of the 70% methanol eluate on a silica gel column with hexane-acetone (3:1) gave 3,3',4',5,6,7,8-heptamethoxyflavone (HMF) and 4',5,6,7,8-pentamethoxyflavone (tangeretin). HMF, tangeretin, and 3',4',5,6,7,8-hexamethoxyflavone (nobiletin), another methoxyflavone contained in orange juice, all increased the steady-state uptake of [3H]vinblastine by Caco-2 cells in a concentration-dependent manner. The order of potency of these compounds at the concentration of 50 µM was tangeretin > HMF > nobiletin. None of these methoxyflavones inhibited 6beta -hydroxylation of testosterone catalyzed by CYP3A4. The ethyl acetate extract of orange juice and these methoxyflavones also increased steady-state [3H]vinblastine uptake by LLC-GA5-COL300 cells (a cell line transfected with human MDR1 cDNA). We conclude that these methoxyflavones enhanced vinblastine uptake by specifically inhibiting drug efflux via P-gp. They may have potential as agents for reversing multidrug resistance or for recovering the bioavailability of certain drugs.

1 This work was supported in part by a grant from the Urakami Foundation, Asahi Breweries Foundation, the SKYLARK Food Science Institute, and grants-in-aid for scientific research from the Ministry of Education, Science, Sports, and Culture, Japan.

0022-3565/00/2931-0230$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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