An Guohua, Wang Xiaodong, Morris Marilyn E
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York, University at Buffalo, Buffalo, New York.
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York, University at Buffalo, Buffalo, New York
Drug Metab Dispos. 2014 Sep;42(9):1357-66. doi: 10.1124/dmd.114.059337. Epub 2014 Jul 7.
Organic anion transporter 1 (OAT1) has been reported to be involved in the nephrotoxicity of many anionic xenobiotics. As current clinically used OAT1 inhibitors are often associated with safety issues, identifying potent OAT1 inhibitors with little toxicity is of great value in reducing OAT1-mediated drug nephrotoxicity. Flavonoids are a class of polyphenolic compounds with exceptional safety records. Our objective was to evaluate the effects of 18 naturally occurring flavonoids, and some of their glycosides, on the uptake of para-aminohippuric acid (PAH) in both OAT1-expressing and OAT1-negative LLC-PK1 cells. Most flavonoid aglycones produced substantial decreases in PAH uptake in OAT1-expressing cells. Among the flavonoids screened, fisetin, luteolin, morin, and quercetin exhibited the strongest effect and produced complete inhibition of OAT1-mediated PAH uptake at a concentration of 50 μM. Further concentration-dependent studies revealed that both morin and luteolin are potent OAT1 inhibitors, with IC50 values of <0.3 and 0.47 μM, respectively. In contrast to the tested flavonoid aglycones, all flavonoid glycosides had negligible or small effects on OAT1. In addition, the role of OAT1 in the uptake of fisetin, luteolin, morin, and quercetin was investigated and fisetin was found to be a substrate of OAT1. Taken together, our results indicate that flavonoids are a novel class of OAT1 modulators. Considering the high consumption of flavonoids in the diet and in herbal products, OAT1-mediated flavonoid-drug interactions may be clinically relevant. Further investigation is warranted to evaluate the nephroprotective role of flavonoids in relation to drug-induced nephrotoxicity mediated by the OAT1 pathway.
据报道，有机阴离子转运体1（OAT1）与许多阴离子外源性物质的肾毒性有关。由于目前临床使用的OAT1抑制剂常常存在安全问题，因此鉴定毒性小的强效OAT1抑制剂对于降低OAT1介导的药物肾毒性具有重要价值。黄酮类化合物是一类具有出色安全记录的多酚化合物。我们的目的是评估18种天然存在的黄酮类化合物及其一些糖苷对表达OAT1和不表达OAT1的LLC-PK1细胞中对氨基马尿酸（PAH）摄取的影响。大多数黄酮苷元在表达OAT1的细胞中使PAH摄取量大幅降低。在筛选的黄酮类化合物中，非瑟酮、木犀草素、桑色素和槲皮素表现出最强的作用，在浓度为50 μM时完全抑制OAT1介导的PAH摄取。进一步的浓度依赖性研究表明，桑色素和木犀草素都是强效OAT1抑制剂，IC50值分别<0.3和0.47 μM。与测试的黄酮苷元相反，所有黄酮糖苷对OAT1的影响可忽略不计或很小。此外，研究了OAT1在非瑟酮、木犀草素、桑色素和槲皮素摄取中的作用，发现非瑟酮是OAT1的底物。综上所述，我们的结果表明黄酮类化合物是一类新型的OAT1调节剂。考虑到饮食和草药产品中黄酮类化合物的高消耗量，OAT1介导的黄酮类化合物与药物的相互作用可能具有临床相关性。有必要进一步研究以评估黄酮类化合物在由OAT1途径介导的药物诱导的肾毒性方面的肾保护作用。
