ABCG2 dysfunction increases serum uric acid by decreased intestinal urate excretion. 2014

Tappei Takada, and Kimiyoshi Ichida, and Hirotaka Matsuo, and Akiyoshi Nakayama, and Keizo Murakami, and Yoshihide Yamanashi, and Hiroshi Kasuga, and Nariyoshi Shinomiya, and Hiroshi Suzuki
a Department of Pharmacy , The University of Tokyo Hospital , Tokyo , Japan.

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.

UI MeSH Term Description Entries
D007413 Intestinal Mucosa Lining of the INTESTINES, consisting of an inner EPITHELIUM, a middle LAMINA PROPRIA, and an outer MUSCULARIS MUCOSAE. In the SMALL INTESTINE, the mucosa is characterized by a series of folds and abundance of absorptive cells (ENTEROCYTES) with MICROVILLI. Intestinal Epithelium,Intestinal Glands,Epithelium, Intestinal,Gland, Intestinal,Glands, Intestinal,Intestinal Gland,Mucosa, Intestinal
D008297 Male Males
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000070997 ATP Binding Cassette Transporter, Subfamily G, Member 2 ATP-binding cassette transporter, sub-family G protein that functions as a high capacity UREA exporter, transporter of STEROLS, and in the absorption and efflux of many drugs. Its efflux activity for ANTINEOPLASTIC AGENTS contributes to DRUG RESISTANCE. It functions as a homodimer and is expressed by cells in a variety of organs, as well as by NEOPLASTIC STEM CELLS. ABCG2 Protein,ABCG2 Transporter,ATP Binding Cassette Transporter, Sub-Family G, Member 2,CD338 Antigen
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D014527 Uric Acid An oxidation product, via XANTHINE OXIDASE, of oxypurines such as XANTHINE and HYPOXANTHINE. It is the final oxidation product of purine catabolism in humans and primates, whereas in most other mammals URATE OXIDASE further oxidizes it to ALLANTOIN. 2,6,8-Trihydroxypurine,Ammonium Acid Urate,Monosodium Urate,Monosodium Urate Monohydrate,Potassium Urate,Sodium Acid Urate,Sodium Acid Urate Monohydrate,Sodium Urate,Sodium Urate Monohydrate,Trioxopurine,Urate,Acid Urate, Ammonium,Acid Urate, Sodium,Acid, Uric,Monohydrate, Monosodium Urate,Monohydrate, Sodium Urate,Urate Monohydrate, Monosodium,Urate Monohydrate, Sodium,Urate, Ammonium Acid,Urate, Monosodium,Urate, Potassium,Urate, Sodium,Urate, Sodium Acid
D051379 Mice The common name for the genus Mus. Mice, House,Mus,Mus musculus,Mice, Laboratory,Mouse,Mouse, House,Mouse, Laboratory,Mouse, Swiss,Mus domesticus,Mus musculus domesticus,Swiss Mice,House Mice,House Mouse,Laboratory Mice,Laboratory Mouse,Mice, Swiss,Swiss Mouse,domesticus, Mus musculus
D055786 Gene Knockout Techniques Techniques to alter a gene sequence that result in an inactivated gene, or one in which the expression can be inactivated at a chosen time during development to study the loss of function of a gene. Gene Knock-Out Techniques,Gene Knock Out,Gene Knock Out Techniques,Gene Knockout,Gene Knock Outs,Gene Knock-Out Technique,Gene Knockout Technique,Gene Knockouts,Knock Out, Gene,Knock Outs, Gene,Knock-Out Technique, Gene,Knock-Out Techniques, Gene,Knockout Technique, Gene,Knockout Techniques, Gene,Knockout, Gene,Knockouts, Gene,Out, Gene Knock,Outs, Gene Knock,Technique, Gene Knock-Out,Technique, Gene Knockout,Techniques, Gene Knock-Out,Techniques, Gene Knockout
D057809 HEK293 Cells A cell line generated from human embryonic kidney cells that were transformed with human adenovirus type 5. 293T Cells,HEK 293 Cell Line,HEK 293 Cells,Human Embryonic Kidney Cell Line 293,Human Kidney Cell Line 293,293 Cell, HEK,293 Cells, HEK,293T Cell,Cell, 293T,Cell, HEK 293,Cell, HEK293,Cells, 293T,Cells, HEK 293,Cells, HEK293,HEK 293 Cell,HEK293 Cell
D018528 ATP-Binding Cassette Transporters A family of MEMBRANE TRANSPORT PROTEINS that require ATP hydrolysis for the transport of substrates across membranes. The protein family derives its name from the ATP-binding domain found on the protein. ABC Transporter,ABC Transporters,ATP-Binding Cassette Transporter,ATP Binding Cassette Transporter,ATP Binding Cassette Transporters,Cassette Transporter, ATP-Binding,Transporter, ABC,Transporter, ATP-Binding Cassette,Transporters, ABC,Transporters, ATP-Binding Cassette

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