The elucidation of cephaloridine-induced nephrotoxicity in cell lines stably expressing organic anion transporters

我们用稳定的细胞系阐明了有机阴离子转运体(OAT)在头孢菌素(CER)肾毒性中的作用。(1)大鼠OAT1和OAT3介导CER摄取及其肾毒性。大鼠OAT1和大鼠OAT3对不同的头孢菌素类抗生素表现出不同的底物识别能力。(2)将hOAT1和hOAT3的Ki值与各种头孢菌素类抗生素的临床血药浓度进行比较，发现hOAT1在体内与各种头孢菌素类抗生素相互作用。(3)大鼠OAT1、hOAT1和hOAT3介导赭曲霉毒素A的转运及其肾毒性。(4)不同的OAT抑制剂倍他米隆、西司他丁、丙磺舒和KW-3902可抑制CER诱导的肾毒性。对这些药物的抑制作用进行动力学分析，并将Ki值与这些药物的临床相关血药浓度进行比较。提示这些抑制剂的分子靶点是倍他米隆、丙磺舒的hOAT1和hOAT3，以及西司他丁的hOAT3。相比之下，KW-3902没有任何临床影响。(5)甲氨蝶呤与非甾体抗炎药相互作用的分子同源性为hOAT3。

We elucidated the role of organic anion transporter (OAT) in cephaloridine (CER)-induced nephrotoxicity using stable cell lines.(1)Rat OAT1 and rat OAT3 mediate CER uptake and its nephrotoxicity. Rat OAT1 and rat OAT3 exhibited distinct substrate recognition against various cephalosporin antibiotics.(2)Comparing the Ki values of hOAT1 and hOAT3 with clinically relevant plasma concentrations of various cephalosporin antibiotics, hOAT1 was shown to interact with various cephalosporin antibiotics in vivo.(3)Rat OAT1, hOAT1 and hOAT3 were shown to mediate ochratoxin A transport and its nephrotoxicity.(4)Various OAT inhibitors, betamipron, cilastatin, probenecid and KW-3902, were shown to inhibit CER-induced nephrotoxicity. The kinetic analysis of the inhibitory effects of these drugs was performed, and the Ki values were compared with clinically relevant plasma concentrations of these drugs. It was suggested that the molecular target of these inhibitors was hOAT1 and hOAT3 for betamipron, probenecid, and hOAT3 for cilastatin. In contrast, KW-3902 did not have any clinical impact.(5)Molecular identity for the drug interaction between methotrexate and nonsteroidal anti-inflammatory drug was identified to be hOAT3.