Takeda M, Tojo A, Sekine T, Hosoyamada M, Kanai Y, Endou H
Department of Pharmacology and Toxicology, Kyorin University School of Medicine, Tokyo, Japan.
Kidney Int. 1999 Dec;56(6):2128-36. doi: 10.1046/j.1523-1755.1999.00789.x.
Role of organic anion transporter 1 (OAT1) in cephaloridine (CER)-induced nephrotoxicity.
Cephaloridine (CER) has been used to elucidate the mechanisms of cephalosporin antibiotic-induced nephrotoxicity. Organic anion transporters have been thought to mediate CER uptake by the proximal tubule. The purpose of this study was to elucidate the possible involvement of organic anion transporter 1 (OAT1) in CER-induced nephrotoxicity.
A mouse terminal proximal straight tubule (S3) cell line stably expressing rat OAT1 (S3 rOAT1) was established and used in this study. The cellular uptake of [14C]-para-aminohippuric acid (PAH), a prototype organic anion, and that of [14C]-CER were measured. The effects of CER on the viability of the cells and the amount of lipid peroxidation were estimated.
S3 rOAT1 expressed a functional organic anion transporter in the cytoplasmic membrane, and exhibited CER uptake activity. CER treatment resulted in a more significant decrease in the viability and a more significant increase in the amount of lipid peroxidation in S3 rOAT1 than in S3 cells transfected with an expression vector lacking the rOAT1 insert. Probenecid, an inhibitor of organic anion transport, and probucol, an antioxidant, significantly suppressed the decrease in viability and increase in the amount of lipid peroxidation in S3 rOAT1 treated with CER. The effects of various cephalosporin antibiotics on the uptake of [14C]PAH were correlated significantly with the effects of these drugs on cell viability.
These results suggest that rOAT1 is, at least in part, responsible for the cellular uptake of CER and therefore CER-induced nephrotoxicity.
有机阴离子转运体1（OAT1）在头孢噻啶（CER）诱导的肾毒性中的作用
头孢噻啶（CER）已被用于阐明头孢菌素抗生素诱导肾毒性的机制。有机阴离子转运体被认为介导近端小管对CER的摄取。本研究的目的是阐明有机阴离子转运体1（OAT1）在CER诱导的肾毒性中可能的作用。
建立并使用稳定表达大鼠OAT1的小鼠终末近端直管（S3）细胞系（S3 rOAT1）。测量原型有机阴离子[14C] - 对氨基马尿酸（PAH）以及[14C] - CER的细胞摄取。评估CER对细胞活力和脂质过氧化量的影响。
S3 rOAT1在细胞质膜中表达功能性有机阴离子转运体，并表现出CER摄取活性。与转染了缺乏rOAT1插入片段的表达载体的S3细胞相比，CER处理导致S3 rOAT1的活力更显著降低，脂质过氧化量更显著增加。有机阴离子转运抑制剂丙磺舒和抗氧化剂普罗布考显著抑制了用CER处理的S3 rOAT1的活力降低和脂质过氧化量增加。各种头孢菌素抗生素对[14C]PAH摄取的影响与这些药物对细胞活力的影响显著相关。
这些结果表明rOAT1至少部分负责CER的细胞摄取，因此也负责CER诱导的肾毒性。
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