期刊
NUCLEOSIDES NUCLEOTIDES & NUCLEIC ACIDS
卷 30, 期 12, 页码 1091-1097出版社
TAYLOR & FRANCIS INC
DOI: 10.1080/15257770.2011.633953
关键词
High-capacity urate exporter; ABC transporter; ABCG2/BCRP; hyperuricemia/gout; urate handling
资金
- Ministry of Education, Culture, Sports, Science and Technology of Japan
- Ministry of Defense of Japan
- Ministry of Health, Labour and Welfare of Japan
- Kawano Masanori Memorial Foundation for Promotion of Pediatrics
- Uehara Memorial Foundation
- Takeda Science Foundation
- Gout Research Foundation of Japan
The ATP-binding cassette, subfamily G, member 2 (ABCG2/BCRP) gene encodes a well-known transporter, which exports various substrates including nucleotide analogs such as 3'-azido-3'-deoxythymidine (AZT). ABCG2 is also located in a gout-susceptibility locus (MIM 138900) on chromosome 4q, and has recently been identified by genome-wide association studies to relate to serum uric acid (SUA) and gout. Becuase urate is structurally similar to nucleotide analogs, we hypothesized that ABCG2 might be a urate exporter. To demonstrate our hypothesis, transport assays were performed with membrane vesicles prepared from ABCG2-overexpressing cells. Transport of estrone-3-sulfate (ES), a typical substrate of ABCG2, is inhibited by urate as well as AZT and ES. ATP-dependent transport of urate was then detected in ABCG2-expressing vesicles but not in control vesicles. Kinetic analysis revealed that ABCG2 is a high-capacity urate transporter that maintained its function even under high-urate concentration. The calculated parameters of ABCG2-mediated transport of urate were a Km of 8.24 +/- 1.44 mM and a Vmax of 6.96 +/- 0.89 nmol/min per mg of protein. Moreover, the quantitative trait locus (QTL) analysis performed in 739 Japanese individuals revealed that a dysfunctional variant of ABCG2 increased SUA as the number of minor alleles of the variant increased (p = 6.60 x 10(-5)). Because ABCG2 is expressed on the apical membrane in several tissues, including kidney, intestine, and liver, these findings indicate that ABCG2, a high-capacity urate exporter, has a physiological role of urate homeostasis in the human body through both renal and extrarenal urate excretion.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据