Investigation of the transport of xanthine dehydrogenase inhibitors by the urate transporter ABCG2
Investigation of the transport of xanthine dehydrogenase inhibitors by the urate transporter ABCG2
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DOI：
10.1016/j.dmpk.2017.11.002
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发表时间：
2018-02-01
影响因子：
2.1
通讯作者：
Ichida, Kimiyoshi
中科院分区：
文献类型：
--
作者：
Nakamura, Makiko;Fujita, Kyoko;Ichida, Kimiyoshi
高尿酸血症会诱发痛风和肾结石，并加速肾脏和心血管疾病的进展。腺苷 5'-三磷酸结合盒亚家族 G 成员 2 (ABCG2) 是一种尿酸转运蛋白，ABCG2 常见的功能失调变异、非功能性 Q126X (rs72552713) 和半功能性 Q141K (rs2231142) 是高尿酸血症和痛风的危险因素。最近的一项全基因组关联研究表明别嘌呤醇（一种抑制黄嘌呤脱氢酶的降血清尿酸药物）是 ABCG2 的有效底物。在本研究中，我们旨在检查黄嘌呤脱氢酶抑制剂通过 ABCG2 的转运。我们的结果表明，ABCG2 转运别嘌呤醇的活性代谢物奥昔嘌呤醇，而别嘌呤醇和新的黄嘌呤脱氢酶抑制剂非布索坦不是 ABCG2 的底物。与模拟囊泡相比，在 ATP 存在下，ABCG2 囊泡转运的奥嘌呤醇量显着增加。由于奥嘌呤醇的半衰期比别嘌呤醇长，别嘌呤醇的黄嘌呤脱氢酶抑制作用主要取决于其代谢物奥昔嘌呤。我们的结果表明，ABCG2 功能障碍患者的血清奥昔嘌呤水平会升高。 (c) 2017 年日本异生素研究会。由爱思唯尔有限公司出版。保留所有权利。
Hyperuricemia induces gout and kidney stones and accelerates the progression of renal and cardiovascular diseases. Adenosine 5'-triphosphate-binding cassette subfamily G member 2 (ABCG2) is a urate transporter, and common dysfunctional variants of ABCG2, non-functional Q126X (rs72552713) and semi-functional Q141K (rs2231142), are risk factors for hyperuricemia and gout. A recent genome wide association study suggested that allopurinol, a serum uric acid-lowering drug that inhibits xanthine dehydrogenase, is a potent substrate of ABCG2. In this study, we aimed to examine the transport of xanthine dehydrogenase inhibitors via ABCG2. Our results show that ABCG2 transports oxypurinol, an active metabolite of allopurinol, whereas allopurinol and febuxostat, a new xanthine dehydrogenase inhibitor, are not substrates of ABCG2. The amount of oxypurinol transported by ABCG2 vesicles significantly increased in the presence of ATP, compared to that observed with mock vesicles. Since the half-life of oxypurinol is longer than that of allopurinol, the xanthine dehydrogenase-inhibiting effect of allopurinol mainly depends on its metabolite, oxypurinol. Our results indicate that the serum level of oxypurinol would increase in patients with ABCG2 dysfunction. (c) 2017 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.