Flavonoids as inhibitors of MRP1-like efflux activity in human erythrocytes.: A structure-activity relationship study

被引:41
作者
Bobrowska-Hägerstrand, M
Wróbel, A
Mrówczynska, L
Söderström, T
Shirataki, Y
Motohashi, N
Molnár, J
Michalak, K
Hägerstrand, H [1 ]
机构
[1] Abo Akad Univ, Dept Biol, FIN-20520 Turku, Finland
[2] Wroclaw Tech Univ, Inst Phys, PL-50370 Wroclaw, Poland
[3] Adam Mickiewicz Univ Poznan, Dept Cytol & Histol, PL-61701 Poznan, Poland
[4] Univ Turku, Turku Ctr Biotechnol, FIN-20520 Turku, Finland
[5] Josai Univ, Fac Pharmaceut Sci, Sakado, Saitama 3500295, Japan
[6] Meiji Pharmaceut Univ, Tokyo 2048588, Japan
[7] Albert Szent Gyorgyi Med Univ, Dept Microbiol, H-6720 Szeged, Hungary
[8] Wroclaw Med Univ, Dept Biophys, Wroclaw, Poland
关键词
multidrug resistance; red blood cell; BCPCF; flavanone; structure-activity analysis; benzbromarone; indomethacin;
D O I
10.3727/000000003108747983
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
The potency of flavonoids (isoflavones, flavones, and flavanones) to inhibit efflux of 2',7'-bis-(carboxypropyl)-5(6)-carboxyfluorescein (BCPCF) from human erythrocytes was investigated. Structure-activity relationship analysis showed that the strongest inhibitors were found among flavanones bearing a hydrophobic prenyl, geranyl, or lavandulyl group at position 8 (and hydroxyl groups at 5 and 7) in ring A. A prenyl group at position 5' or stilbene at positions 4'-5' in ring B further seemed to increase inhibitor potency. The most efficient flavanones, euchrestaflavanone A and sophoraflavanone H, were similar to20 times more efficient than genistein, and induced 50% inhibition of BCPCF efflux (IC50) at 3 muM (60 min, 37degreesC). This is comparable to IC50 of benzbromarone (4 muM) and lower than IC50 of indomethacin (10 muM), both known MRP1 (ABCC1) inhibitors. It is suggested that BCPCF efflux is mainly due to MRP1 activity. Our results indicate that flavonoid molecular structure provides a promising base for development of potent MRP1 inhibitors.
引用
收藏
页码:463 / 469
页数:7
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