Flavonoids Are Inhibitors of Human Organic Anion Transporter 1 (OAT1)-Mediated Transport
Flavonoids Are Inhibitors of Human Organic Anion Transporter 1 (OAT1)-Mediated Transport
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DOI：
10.1124/dmd.114.059337
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发表时间：
2014-09-01
影响因子：
3.9
通讯作者：
Morris, Marilyn E.
中科院分区：
文献类型：
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作者：
An, Guohua;Wang, Xiaodong;Morris, Marilyn E.
有机阴离子转运蛋白1 （OAT1）已被报道参与了许多阴离子外源药物的肾毒性。由于目前临床使用的OAT1抑制剂往往与安全性问题有关，因此，确定毒性小的强效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特殊安全记录的多酚类化合物。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苷对表达oat1和oat1阴性的LLC-PK1细胞对对氨基马尿酸（PAH）摄取的影响。大多数类黄酮苷元在表达oat1的细胞中产生PAH摄取的显著降低。在所筛选的黄酮类化合物中，非瑟酮、木犀草素、桑皮素和槲皮素的作用最强，在50 μ m浓度下完全抑制OAT1介导的多环芳烃摄取。进一步的浓度依赖性研究表明，桑皮素和木犀草素都是有效的OAT1抑制剂，IC50值为
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 mu M. Further concentration-dependent studies revealed that both morin and luteolin are potent OAT1 inhibitors, with IC50 values of