論文 - 詳細
| RRC ID | 39645 |
|---|---|
| 著者 | Takanaga H, Ohnishi A, Yamada S, Matsuo H, Morimoto S, Shoyama Y, Ohtani H, Sawada Y. |
| タイトル | Polymethoxylated flavones in orange juice are inhibitors of P-glycoprotein but not cytochrome P450 3A4. |
| ジャーナル | J Pharmacol Exp Ther |
| Abstract |
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 [(3)H]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 [(3)H]vinblastine but significantly increased the steady-state uptake, as did cyclosporin A (20 microM), an inhibitor of P-gp. No significant effect on the uptake of 3-O-[(3)H]methylglucose or [(14)C]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 [(3)H]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 [(3)H]vinblastine by Caco-2 cells in a concentration-dependent manner. The order of potency of these compounds at the concentration of 50 microM 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 [(3)H]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. |
| 巻・号 | 293(1) |
| ページ | 230-6 |
| 公開日 | 2000-4-1 |
| PMID | 10734174 |
| MeSH | ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors* Animals Antineoplastic Agents, Phytogenic / metabolism Beverages / analysis* Caco-2 Cells Cell Survival / drug effects Citrus / chemistry* Cyclosporine / pharmacology Cytochrome P-450 CYP3A Cytochrome P-450 Enzyme Inhibitors* Flavones* Flavonoids / analysis Flavonoids / chemistry Flavonoids / pharmacology* Humans Hydroxylation LLC-PK1 Cells Liver / drug effects Liver / enzymology Mixed Function Oxygenases / antagonists & inhibitors* Solvents Swine Testosterone / metabolism Vinblastine / metabolism |
| IF | 3.561 |
| 引用数 | 111 |
| WOS 分野 | PHARMACOLOGY & PHARMACY |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | Patent(IFI CLAIMS) |
| 各媒体での言及数の合計 | 7 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | LLC-GA5-CoL300(RCB0872) |