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.

Urate Transporters: Transforming the Face of Hyperuricemia and Gout

“…Second, and in contrast, the risk allele for BCRP was positively associated with both underexcretion and normoexcretion, but the association was much stronger with normoexcretion. The importance of the latter observation is that it provides confirmation of work reported from Japan 11,12 , implicating the polymorphism in the ABCG2 gene as a risk allele for hyperuricemia/gout by a previously undescribed mechanism: reduced intestinal urate disposal, thus placing a greater burden on the kidneys to assure uric acid balance. The consequence is hyperuricemia and an increased risk for gout, despite urinary excretion of high normal or even increased amounts of uric acid.…”

“…The study by Torres, et al 2 , as well as the research of others directly 11,12 or indirectly 14,15 , address both of the progress-limiting issues identified above. Distinguishing methodological features of the Torres, et al 2 study include unusually careful control of diet, medications, and sample accession, permitting accurate classification of the daily urinary uric acid excretion status of 104 ambulatory Spanish patients with primary gout (i.e., gout unrelated to a known enzymopathy or secondary to another medical condition); comparison of the patients with gout versus normal Spanish population controls with regard to the frequencies of 5 single nucleotide polymorphisms (SNP) associated, in other population groups, with urate transporter alleles altering the risk for hyperuricemia and gout; and creation of a risk index to assess possible interactions among risk alleles for the urate transporters URAT1 (encoded by gene SLC22A12), GLUT9, and BCRP.…”

“…First, some urate transporters, notably the secretory transporter BCRP (encoded by the ABCG2 gene), are expressed in the gut as well as in the kidney and play a role in active intestinal elimination of urate 9,11,12 . Second, genes encoding both net reabsorptive and net secretory urate transporters are polymorphic, showing DNA sequence variations that are common, some of which are also identifiable as risk (or protective) alleles with respect to their higher (or lower) frequency of appearance in hyperuricemic persons/patients with gout than in corresponding persons without gout 9,11,13 .…”

Drug Transporters and Na+/H+Exchange Regulatory Factor PSD-95/Drosophila Discs Large/ZO-1 Proteins

“…In the case of sunitinib, carriers of BCRP polymorphisms also experience a higher incidence of sunitinib-induced toxicity (Mizuno et al, 2012). In addition to altering pharmacokinetics and pharmacodynamics, BCRP polymorphisms are associated with disease states such as Alzheimer's disease and gout (Matsuo et al, 2011b;Feher et al, 2013;Takada et al, 2014). The association between BCRP and these disease states is hypothesized to be secondary to BCRP dependent handling of amyloid beta in Alzheimer's disease and uric acid in patients with gout (Matsuo et al, 2011a,b;Abuznait and Kaddoumi, 2012).…”

Uric acid transporter inhibitors for gout

“…The important drug transporter breast cancer resistance protein (BCRP, encoded by the ABCG2 gene) is highly expressed on the apical surface of intestinal epithelial cells and is also an important urate transporter involved in intestinal urate secretion [9][10][11][12]. Dietary purines are imported from the lumen of intestinal enterocytes by the nucleoside transporter CNT2/SLC28A2, which are then converted to uric acid by intestinal xanthine oxidase.…”