Jung Kyu Yong, Takeda Michio, Shimoda Minoru, Narikawa Shinichi, Tojo Akihiro, Kim Do Kyung, Chairoungdua Arthit, Choi Bong Kyu, Kusuhara Hiroyuki, Sugiyama Yuichi, Sekine Takashi, Endou Hitoshi
Department of Pharmacology and Toxicology, Kyorin University School of Medicine, Mitaka-shi, Tokyo, Japan.
Life Sci. 2002 Mar 8;70(16):1861-74. doi: 10.1016/s0024-3205(02)01500-x.
This study was performed to elucidate the possible involvement of organic anion transporter 3 (OAT3) in cephaloridine (CER)-induced nephrotoxicity and compare the substrate specificity between rOAT3 and rat OAT1 (rOAT1) for various cephalosporin antibiotics, using proximal tubule cells stably expressing rOAT3 (S2 rOAT3) and rOAT1 (S2 rOAT1). S2 rOAT3 exhibited a CER uptake and a higher susceptibility to CER cytotoxicity than did mock, which was recovered by probenecid. Various cephalosporin antibiotics significantly inhibited both estrone sulfate uptake in S2 rOAT3 and para-aminohippuric acid uptake in S2 rOAT1. The Ki values of CER, cefoperazone, cephalothin and cefazolin for rOAT3- and rOAT1-mediated organic anion transport ranged from 0.048 to 1.14 mM and from 0.48 to 1.32 mM, respectively. These results suggest that rOAT3, at least in part, mediates CER uptake and CER-induced nephrotoxicity as rOAT1. There was some difference of affinity between rOAT3 and rOAT1 for cephalosporin antibiotics.
本研究旨在阐明有机阴离子转运体3（OAT3）在头孢菌素（CER）诱导的肾毒性中可能的作用，并使用稳定表达rOAT3（S2 rOAT3）和rOAT1（S2 rOAT1）的近端小管细胞，比较rOAT3和大鼠OAT1（rOAT1）对各种头孢菌素抗生素的底物特异性。与mock相比，S2 rOAT3表现出CER摄取以及对CER细胞毒性更高的敏感性，丙磺舒可恢复这种敏感性。各种头孢菌素抗生素均显著抑制S2 rOAT3中硫酸雌酮的摄取以及S2 rOAT1中对氨基马尿酸的摄取。CER、头孢哌酮、头孢噻吩和头孢唑林对rOAT3和rOAT1介导的有机阴离子转运的Ki值分别为0.048至1.14 mM和0.48至1.32 mM。这些结果表明，rOAT3至少部分地介导CER摄取和CER诱导的肾毒性，与rOAT1相同。rOAT3和rOAT1对头孢菌素抗生素的亲和力存在一些差异。
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