Flavonoids as Inhibitors of MRP1-Like Efflux Activity in Human Erythrocytes. A Structure–Activity Relationship Study
Abstract: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 ∼20 times more efficient than genistein, and induced 50% inhibition of BCPCF efflux (IC50) at 3 μM (60 min, 37°C). This is comparable to IC50 of benzbromarone (4 μM) and lower than IC50 of indomethacin (10 μM), 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.
Document Type: Research Article
Affiliations: 1: *Department of Biology, Åbo Akademi University, FIN-20520 Åbo/Turku, Finland 2: †Institute of Physics, Wrocław University of Technology, PL-50370 Wrocław, Poland 3: ‡Department of Cytology and Histology, A. Mickiewicz University, PL-61701, Poznan´, Poland 4: ¶Faculty of Pharmaceutical Sciences, Josai University, Sakado, Saitama, 350-0295 Japan 5: #Meiji Pharmaceutical University, Tokyo, 204-8588, Japan 6: **Department of Microbiology, Albert Szent-Györgyi Medical University, H-6720 Szeged, Hungary 7: ††Department of Biophysics, Wrocław Medical University, Poland
Publication date: January 1, 2003
- Formerly: Oncology Research Incorporating Anti-Cancer Drug Design
Oncology Research Featuring Preclinical and Clincal Cancer Therapeutics publishes research of the highest quality that contributes to an understanding of cancer in areas of molecular biology, cell biology, biochemistry, biophysics, genetics, biology, endocrinology, and immunology, as well as studies on the mechanism of action of carcinogens and therapeutic agents, reports dealing with cancer prevention and epidemiology, and clinical trials delineating effective new therapeutic regimens.