**4. Relevance of ABCG2 in Extrarenal Urate Elimination**

As earlier studies indicated that ABCG2 is also expressed in the liver [58] and intestine [42] and that ABCG2 may function as a urate transporter [50,52], it was reasonable to speculate that ABCG2 plays a role in extrarenal urate excretion possibly via the bile or intestine [82]. However, accurate non-invasive measurements of intestinal/biliary urate secretion are not possible in humans because the secreted urate is largely metabolized by the bacterial flora in the intestine. Therefore, the role of ABCG2 in extrarenal urate secretion was revealed in animal experiments using the in situ intestinal "closed-loop" perfusion method [51,71]. Since most vertebrates, including rodents used for animal studies, express the enzyme uricase which converts uric acid to allantoin and which has been lost during human evolution [83], a direct relation of results from animal experiments studying urate metabolism and urate transport to the human organism is inadequate. To account for that, rodents used in both studies were treated with the uricase inhibitor oxonate, a pharmacological intervention that increased the serum urate levels in mice and rats to the magnitude of serum urate levels in humans [51,71]. By administration of radioactive labeled uric acid, Hosomi and colleagues demonstrated that, in addition to the substantial fraction of renal urate elimination [51], there is direct urate excretion via the intestine (mainly in the ileum) and only minor urate excretion via the bile [51,71]. These findings, therefore, suggest that the intestine is the main site of extrarenal urate excretion. In the intestine of mice, ABCG2 expression is mainly located at the villi brush border of epithelial cells of the ileum and the jejunum [40]. Interestingly, in this study, the observed overall expression levels of the protein in the intestine are much higher than in the kidney. In rats, ABCG2 expression in the gut was found to further increase in response to increased blood urate concentrations after oxonate treatment [84]. To study the contribution of ABCG2 in intestinal urate excretion (and renal urate excretion which was already discussed above), oxonate-treated ABCG2 knockout mice were used [51,71] and showed a reduction in intestinal urate elimination by roughly 40–50%. These findings also suggest that other yet unknown transporters besides ABCG2 are involved in intestinal urate secretion [51,71]. A similar severe loss in intestinal urate elimination was also observed in the aforementioned study by Hogue and colleagues in an orthologous Q140K knock-in mouse model but in absence of the uricase inhibitor oxonate [40]. Consistent with these data, Q140K knock-in in mice resulted in a marked reduction in intestinal ABCG2 expression. In contrast, only subtle changes in urate elimination and ABCG2 expression were observed in the kidney in the same knock-in mouse model. These results are further supported by the observation of other authors, which indicate that the ABCG2 Q141K polymorphism and fractional renal clearance both contribute significantly but independently to the risk of hyperuricemia in humans [73]. In addition, impaired intestinal urate excretion induced by the orthologous murine Q140K mutation or complete ABCG2 knockout may explain hyperuricemia despite unaltered renal urate excretion in the respective mouse models [71,85,86] as well as in human individuals carrying the Q141K polymorphism [40]. However, due to the rise in serum urate levels (sUA) caused by the lack of intestinal urate secretion, an indirect increase in the fraction of filtered urate load (FEUA) could be expected in patients with ABCG2 dysfunction although this was not observed in the previously mentioned study [40]. In addition, ABCG2-mediated intestinal urate elimination appears to play an important role

in compensating for the loss of renal urate elimination in chronic kidney disease [35]. Taken together, recent publications indicate that the major site of action of the ABCG2 transporter is regulating urate homeostasis in the intestine.
