Organic anion transporters involved in the excretion of bestatin in the kidney

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• 作者：Yanna Zhu^a ; ^{zhuyanna.1986@163.com} ; Qiang Meng^a ; ^c ; ^{mengq531@yahoo.cn} ; Changyuan Wang^a ; ^c ; ^{wangcyuan@163.com} ; Qi Liu^a ; ^c ; ^{llaqii@yahoo.com.cn} ; Huijun Sun^a ; ^c ; ^{sunhuijun@hotmail.com} ; Taiichi Kaku^b ; ^{Tai_san@126.com} ; Kexin Liu^a ; ^c ; ^{kexinliu@dlmedu.edu.cn}
• 关键词：OATs ; organic anion transporters ; OCTs ; organic cation transporters ; PEPT 1 ; peptide transporter 1 ; PAH ; p-aminohippuric acid ; PCG ; penicillin-G ; HEK293 cells ; human embryonic kidney cells ; AUC ; area under the plasma concentration&ndash ; time curve ; CL ; cl
• 刊名：Peptides
• 出版年：2012
• 期刊代码：59_01969781
• 类别：neu
• 出版时间：February, 2012
• 卷：33
• 期：2
• 页码：265-271
• 文件大小：724 K

摘要

Bestatin, a dipeptide, a low molecular weight aminopeptidase inhibitor, has been demonstrated to be an immunomodulator with an antitumor activity. However, the transporter-mediated renal excretion of bestatin is not fully understood. The purpose of this study was to elucidate the transporter-mediated renal excretion mechanism for bestatin. The plasma concentration of bestatin was increased markedly and both the accumulative renal excretion and renal clearance of bestatin were decreased significantly after intravenous administration of bestatin in combination with probenecid. p-Aminohippuric acid (PAH), a substrate of organic anion transporter (OAT) 1, benzylpenicillin (PCG), a substrate of OAT3 and JBP485, a substrate of OAT1 and OAT3, reduced the uptake of bestatin in rat kidney slices and in hOAT1- or hOAT3-HEK 293 cells. The accumulation of bestatin in hOAT1-HEK and hOAT3-HEK 293 cells was significantly greater than that in vector-HEK, and the K_m and V_max were 0.679 卤 0.007 mM and 0.807 卤 0.006 nmol/mg protein/30 s for OAT1, 0.632 卤 0.014 mM and 1.303 卤 0.015 nmol/mg protein/30 s for OAT3 respectively. PAH and JBP485 inhibited significantly the uptake of bestatin in hOAT1-HEK with the K_i values of 92 卤 9 渭M and 197 卤 21 渭M; and PCG, JBP485 inhibited significantly the uptake of bestatin in hOAT3-HEK 293 cells with the K_i values of 88 卤 12 渭M and 160 卤 16 渭M. Our results are novel in demonstrating for the first time that OAT1 and OAT3 are involved in the renal excretion of bestatin.