Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University Kita-12-jo, Nishi-6-chome, Kita-ku, Sapporo, Japan.
J Pharm Pharm Sci. 2012;15(2):295-304. doi: 10.18433/j3w896.
Uric acid is thought to be one of the most important antioxidants in human biological fluids. Intestinal ischemia-reperfusion (I/R) is an important factor associated with high rates of morbidity and mortality. Reactive oxygen species (ROS) are responsible for intestinal I/R injury. The aim of this study was to clarify the efflux for uric acid from the intestine after intestinal I/R.
We used intestinal ischemia-reperfusion (I/R) model rats. Serosal to mucosal flux for [¹⁴C]-uric acid was assessed by using Ussing-type diffusion chambers. BCRP/Bcrp expression was assessed by Western blot analysis. Caco-2 cells were used for a model of the intestinal epithelium, and rotenone was used as a mitochondrial dysfunction inducer.
Serosal to mucosal flux for uric acid was increased after intestinal I/R, and that for mannitol was also increased. Ko143, which is a BCRP inhibitor, did not affect the uric acid transport. The decreasing uric acid transport mediated by Bcrp was caused by decrease in the level of Bcrp homodimer, bridged by an S-S bond. The suppression of Bcrp S-S bond formation was associated with mitochondrial dysfunction. Moreover, BCRP S-S bond formation activity was decreased by rotenone in Caco-2 cells.
Serosal to mucosal flux for uric acid is significantly increased via the paracelluler route, but that via the transcellular route mediated by Bcrp is decreased after intestinal I/R. The decreasing uric acid flux mediated by Bcrp is caused by suppression of Bcrp S-S bond formation. This suppression of Bcrp S-S bond formation may be related to mitochondrial dysfunction.
尿酸被认为是人类生物体液中最重要的抗氧化剂之一。肠缺血再灌注（I/R）是与高发病率和死亡率相关的重要因素。活性氧（ROS）是肠 I/R 损伤的原因。本研究旨在阐明肠 I/R 后尿酸从肠道的流出情况。
我们使用肠缺血再灌注（I/R）模型大鼠。通过使用 Ussing 型扩散室评估[¹⁴C]-尿酸的肠腔到黏膜侧通量。通过 Western blot 分析评估 BCRP/Bcrp 的表达。Caco-2 细胞用于肠上皮模型，并用鱼藤酮作为线粒体功能障碍诱导剂。
肠 I/R 后尿酸的肠腔到黏膜侧通量增加，甘露醇的通量也增加。BCRP 抑制剂 Ko143 对尿酸转运没有影响。BCrp 介导的尿酸转运减少是由于 S-S 键桥联的 Bcrp 同源二聚体水平降低所致。BCrp S-S 键形成的抑制与线粒体功能障碍有关。此外，鱼藤酮可降低 Caco-2 细胞中 BCRP 的 S-S 键形成活性。
肠 I/R 后，尿酸通过细胞旁途径的肠腔到黏膜侧通量显著增加，但通过 Bcrp 介导的细胞内途径的通量减少。BCrp 介导的尿酸通量减少是由于 Bcrp S-S 键形成的抑制所致。BCrp S-S 键形成的抑制可能与线粒体功能障碍有关。
