Takada Tappei, Ichida Kimiyoshi, Matsuo Hirotaka, Nakayama Akiyoshi, Murakami Keizo, Yamanashi Yoshihide, Kasuga Hiroshi, Shinomiya Nariyoshi, Suzuki Hiroshi
a Department of Pharmacy , The University of Tokyo Hospital , Tokyo , Japan.
Nucleosides Nucleotides Nucleic Acids. 2014;33(4-6):275-81. doi: 10.1080/15257770.2013.854902.
ATP-binding cassette transporter G2 (ABCG2), also known as breast cancer resistance protein (BCRP), is identified as a high-capacity urate exporter and its dysfunction has an association with serum uric acid (SUA) levels and gout/hyperuricemia risk. However, pathophysiologically important pathway(s) responsible for the ABCG2-mediated urate excretion were unknown. In this study, we investigated how ABCG2 dysfunction affected the urate excretion pathways. First, we revealed that mouse Abcg2 mediates urate transport using the membrane vesicle system. The export process by mouse Abcg2 was ATP-dependent and not saturable under the physiological concentration of urate. Then, we characterized the excretion of urate into urine, bile, and intestinal lumen using in vivo mouse model. SUA of Abcg2-knockout mice was significantly higher than that of control mice. Under this condition, the renal urate excretion was increased in Abcg2-knockout mice, whereas the urate excretion from the intestine was decreased to less than a half. Biliary urate excretion showed no significant difference regardless of Abcg2 genotype. From these results, we estimated the relative contribution of each pathway to total urate excretion; in wild-type mice, the renal excretion pathway contributes approximately two-thirds, the intestinal excretion pathway contributes one-third of the total urate excretion, and the urate excretion into bile is minor. Decreased intestinal excretion could account for the increased SUA of Abcg2-knockout mice. Thus, ABCG2 is suggested to have an important role in extra-renal urate excretion, especially in intestinal excretion. Accordingly, increased SUA in patients with ABCG2 dysfunction could be explained by the decreased excretion of urate from the intestine.
ATP结合盒转运体G2（ABCG2），也被称为乳腺癌耐药蛋白（BCRP），被鉴定为一种高容量尿酸盐转运蛋白，其功能障碍与血清尿酸（SUA）水平及痛风/高尿酸血症风险相关。然而，负责ABCG2介导的尿酸排泄的病理生理学重要途径尚不清楚。在本研究中，我们调查了ABCG2功能障碍如何影响尿酸排泄途径。首先，我们利用膜囊泡系统揭示了小鼠Abcg2介导尿酸转运。小鼠Abcg2的转运过程是ATP依赖的，并且在生理浓度的尿酸条件下不饱和。然后，我们使用体内小鼠模型对尿酸向尿液、胆汁和肠腔的排泄进行了表征。Abcg2基因敲除小鼠的SUA显著高于对照小鼠。在此条件下，Abcg2基因敲除小鼠的肾脏尿酸排泄增加，而肠道尿酸排泄减少至不到一半。无论Abcg2基因型如何，胆汁尿酸排泄均无显著差异。根据这些结果，我们估计了各途径对总尿酸排泄的相对贡献；在野生型小鼠中，肾脏排泄途径约占总尿酸排泄的三分之二，肠道排泄途径占三分之一，而胆汁尿酸排泄较少。肠道排泄减少可解释Abcg2基因敲除小鼠SUA的增加。因此，ABCG2被认为在肾外尿酸排泄中起重要作用，尤其是在肠道排泄中。相应地，ABCG2功能障碍患者SUA升高可由肠道尿酸排泄减少来解释。
