title: ABCG2 dysfunction increases serum uric acid by decreased intestinal urate excretion.
abstract: 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.
authors.affiliation: a Department of Pharmacy , The University of Tokyo Hospital , Tokyo , Japan.
authors.forename: Tappei
authors.initials: T
authors.lastname: Takada
authors.forename: Kimiyoshi
authors.initials: K
authors.lastname: Ichida
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Matsuo
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Nakayama
authors.forename: Keizo
authors.initials: K
authors.lastname: Murakami
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Yamanashi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kasuga
authors.forename: Nariyoshi
authors.initials: N
authors.lastname: Shinomiya
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Suzuki
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000172:deficiency / Q000235:genetics*; D000818:Animals; D055786:Gene Knockout Techniques; D057809:HEK293 Cells; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D008297:Male; D051379:Mice; D014527:Uric Acid / Q000097:blood* / Q000378:metabolism
chemical_list: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C501412:Abcg2 protein, mouse; D014527:Uric Acid
keywords: ABC transporter; Urate transporter; extra-renal excretion; gut excretion