Kato Yukio, Kuge Kiyoka, Kusuhara Hiroyuki, Meier Peter J, Sugiyama Yuichi
Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyoi-ku, Tokyo 113-0033, Japan.
J Pharmacol Exp Ther. 2002 Aug;302(2):483-9. doi: 10.1124/jpet.102.033878.
This study was aimed at clarifying the gender differences in the urinary excretion of organic anions and the gene expression of organic anion transporters in rats. The renal clearance with regard to the plasma concentration (CL(urine,p)) of taurocholate, dibromosulfophthalein (DBSP), and zenarestat, all substrates and/or inhibitors of organic anion transporting polypeptide 1 (Oatp1), was much higher in female than in male rats. The following results imply that the transport system(s) for the reabsorption of zenarestat across the luminal side exhibits a gender difference: 1) the renal uptake clearance assessed by an in vivo integration plot analysis of zenarestat from the blood side does not show any clear gender differences; 2) the renal clearance with regard to the kidney concentration (CL(urine,k)) of zenarestat in female rats was approximately 30 times higher than in male rats; and 3) both CL(urine,p) and CL(urine,k) were increased in male rats by the coinfusion of DBSP, which is an inhibitor of organic anion transporters. Northern and Western blot analyses confirmed a previous finding that the gene expression of Oatp1, which is localized at the apical plasma membrane of the kidney, was much higher in the kidneys of male rats. Overall, a gender difference in urinary excretion is commonly observed for several organic anions, including Oatp1 substrates and inhibitors, and Oatp1 and/or transporters that have a similar substrate specificity to Oatp1 could be involved in such a phenomenon involving its substrates.
本研究旨在阐明大鼠体内有机阴离子尿排泄及有机阴离子转运体基因表达的性别差异。牛磺胆酸盐、二溴磺酚酞（DBSP）和泽那司他均为有机阴离子转运多肽1（Oatp1）的底物和/或抑制剂，雌性大鼠对它们的肾清除率（相对于血浆浓度的CL(urine,p)）远高于雄性大鼠。以下结果表明泽那司他经管腔侧重吸收的转运系统存在性别差异：1）通过对泽那司他血侧进行体内积分图分析评估的肾摄取清除率未显示出明显的性别差异；2）雌性大鼠中泽那司他相对于肾脏浓度的肾清除率（CL(urine,k)）比雄性大鼠高约30倍；3）同时输注有机阴离子转运体抑制剂DBSP可使雄性大鼠的CL(urine,p)和CL(urine,k)均升高。Northern印迹和Western印迹分析证实了先前的一项发现，即定位于肾顶端质膜的Oatp1在雄性大鼠肾脏中的基因表达水平更高。总体而言，包括Oatp1底物和抑制剂在内的几种有机阴离子在尿排泄中普遍存在性别差异，与Oatp1具有相似底物特异性的Oatp1和/或转运体可能参与了涉及其底物的这一现象。
