Polymethoxylated flavones in orange juice are inhibitors of P- glycoprotein but not cytochrome P450 3A4

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

Research output: Contribution to journalArticle

121 Citations (Scopus)

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 [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 6β-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.

Original languageEnglish
Pages (from-to)230-236
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Volume293
Issue number1
Publication statusPublished - 2000 Apr
Externally publishedYes

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Flavones
Cytochrome P-450 CYP3A
Vinblastine
P-Glycoprotein
Caco-2 Cells
Methanol
Pharmaceutical Preparations
3-O-Methylglucose
Silica Gel
Multiple Drug Resistance
Hexanes
Hydroxylation
Acetone
Phenylalanine
Cytochrome P-450 Enzyme System
Cyclosporine
Biological Availability
Isoenzymes
Testosterone
Complementary DNA

ASJC Scopus subject areas

  • Pharmacology

Cite this

Takanaga, H., Ohnishi, A., Yamada, S., Matsuo, H., Morimoto, S., Shoyama, Y., ... Sawada, Y. (2000). Polymethoxylated flavones in orange juice are inhibitors of P- glycoprotein but not cytochrome P450 3A4. Journal of Pharmacology and Experimental Therapeutics, 293(1), 230-236.

Polymethoxylated flavones in orange juice are inhibitors of P- glycoprotein but not cytochrome P450 3A4. / Takanaga, Hitomi; Ohnishi, Ayako; Yamada, Shiho; Matsuo, Hirotami; Morimoto, Satoshi; Shoyama, Yukihiro; Ohtani, Hisakazu; Sawada, Yasufumi.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 293, No. 1, 04.2000, p. 230-236.

Research output: Contribution to journalArticle

Takanaga, H, Ohnishi, A, Yamada, S, Matsuo, H, Morimoto, S, Shoyama, Y, Ohtani, H & Sawada, Y 2000, 'Polymethoxylated flavones in orange juice are inhibitors of P- glycoprotein but not cytochrome P450 3A4', Journal of Pharmacology and Experimental Therapeutics, vol. 293, no. 1, pp. 230-236.
Takanaga, Hitomi ; Ohnishi, Ayako ; Yamada, Shiho ; Matsuo, Hirotami ; Morimoto, Satoshi ; Shoyama, Yukihiro ; Ohtani, Hisakazu ; Sawada, Yasufumi. / Polymethoxylated flavones in orange juice are inhibitors of P- glycoprotein but not cytochrome P450 3A4. In: Journal of Pharmacology and Experimental Therapeutics. 2000 ; Vol. 293, No. 1. pp. 230-236.
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N2 - 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 6β-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.

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