title: ABCG2 is a high-capacity urate transporter and its genetic impairment increases serum uric acid levels in humans.
abstract: 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 × 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.
authors: Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan.
authors: Akiyoshi
authors: A
authors: Nakayama
authors: Hirotaka
authors: H
authors: Matsuo
authors: Tappei
authors: T
authors: Takada
authors: Kimiyoshi
authors: K
authors: Ichida
authors: Takahiro
authors: T
authors: Nakamura
authors: Yuki
authors: Y
authors: Ikebuchi
authors: Kousei
authors: K
authors: Ito
authors: Tatsuo
authors: T
authors: Hosoya
authors: Yoshikatsu
authors: Y
authors: Kanai
authors: Hiroshi
authors: H
authors: Suzuki
authors: Nariyoshi
authors: N
authors: Shinomiya
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D006801:Humans; D033461:Hyperuricemia / Q000097:blood / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics*; D027361:Organic Anion Transporters / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D014527:Uric Acid / Q000097:blood*
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D009363:Neoplasm Proteins; D027361:Organic Anion Transporters; C103862:urate transporter; D014527:Uric Acid