Deguchi Tsuneo, Isozaki Kouya, Yousuke Kouno, Terasaki Tetsuya, Otagiri Masaki
Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
J Neurochem. 2006 Feb;96(4):1051-9. doi: 10.1111/j.1471-4159.2005.03550.x.
Renal failure causes multiple physiological changes involving CNS dysfunction. In cases of uremia, there is close correlation between plasma levels of uremic toxins [e.g. 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF), hippurate (HA) and indoleacetate (IA)] and the degree of uremic encephalopathy, suggesting that uremic toxins are involved in uremic encephalopathy. In order to evaluate the relevance of uremic toxins to CNS dysfunction, we investigated directional transport of uremic toxins across the blood-brain barrier (BBB) using in vivo integration plot analysis and the brain efflux index method. We observed saturable efflux transport of [(3)H]CMPF, [(14)C]HA and [(3)H]IA, which was inhibited by probenecid. For all uremic toxins evaluated, apparent efflux clearance across the BBB was greater than apparent influx clearance, suggesting that these toxins are predominantly transported from the brain to blood across the BBB. Saturable efflux transport of [(3)H]CMPF, [(14)C]HA and [(3)H]IA was completely inhibited by benzylpenicillin, which is a substrate of rat organic anion transporter 3 (rOat3). Taurocholate and digoxin, which are common substrates of rat organic anion transporting polypeptide (rOatp), partially inhibited the efflux of [(3)H]CMPF. Transport experiments using a Xenopus laevis oocyte expression system revealed that CMPF, HA and IA are substrates of rOat3, and that CMPF (but not HA or IA) is a substrate of rOap2. These results suggest that rOat3 mediates brain-to-blood transport of uremic toxins, and that rOatp2 is involved in efflux of CMPF. Thus, conditions typical of uremia can cause inhibition of brain-to-blood transport involving rOat3 and/or rOatp2, leading to accumulation of endogenous metabolites and drugs in the brain.
肾衰竭会引发多种涉及中枢神经系统功能障碍的生理变化。在尿毒症病例中，尿毒症毒素（如3-羧基-4-甲基-5-丙基-2-呋喃丙酸酯（CMPF）、马尿酸盐（HA）和吲哚乙酸（IA））的血浆水平与尿毒症脑病的严重程度密切相关，这表明尿毒症毒素与尿毒症脑病有关。为了评估尿毒症毒素与中枢神经系统功能障碍的相关性，我们使用体内积分图分析和脑外排指数法研究了尿毒症毒素跨血脑屏障（BBB）的定向转运。我们观察到[(3)H]CMPF、[(14)C]HA和[(3)H]IA的饱和外排转运，丙磺舒可抑制这种转运。对于所有评估的尿毒症毒素，其跨血脑屏障的表观外排清除率大于表观内流清除率，这表明这些毒素主要通过血脑屏障从脑向血液转运。[(3)H]CMPF、[(14)C]HA和[(3)H]IA的饱和外排转运被苄青霉素完全抑制，苄青霉素是大鼠有机阴离子转运体3（rOat3）的底物。牛磺胆酸盐和地高辛是大鼠有机阴离子转运多肽（rOatp）的常见底物，它们部分抑制[(3)H]CMPF的外排。使用非洲爪蟾卵母细胞表达系统进行的转运实验表明，CMPF、HA和IA是rOat3的底物，并且CMPF（但不是HA或IA）是rOap2的底物。这些结果表明，rOat3介导尿毒症毒素从脑到血液的转运，并且rOatp2参与CMPF的外排。因此，尿毒症典型的情况可导致涉及rOat3和/或rOatp2的脑到血液转运受到抑制，从而导致内源性代谢物和药物在脑内蓄积。
