Role of the ABCG2 transporter in the biodistribution of the food-borne uremic toxin p-cresyl sulfate

The ATP-binding cassette transporter G2 (ABCG2) is a membrane transporter that conditions pharmacokinetics, systemic exposure, and milk secretion of drugs, natural and food-derived compounds, including gut-derived metabolites. p-Cresyl sulfate (pCS), a well-known uremic toxin, is the main metabolite of p-Cresol (pC), produced from dietary aromatic amino acids by gut microbiota. We aimed to characterize the in vitro and in vivo interaction of pCS with the ABCG2 transporter. Using MDCK–II cells overexpressing the transporter, we found that pCS is an in vitro substrate of ABCG2. Furthermore, using wild-type and Abcg2−/− mice, we showed that plasma AUC0−240 min for Abcg2−/− was almost 1.6-fold higher than for wild-type mice. Regarding tissue distribution, the liver, kidney, small intestine, testis, and spleen from Abcg2−/− mice showed significantly higher pCS levels versus the wild-type group. Moreover, pCS accumulation in small intestine content retrieved from wild-type mice was 2-fold higher than in the Abcg2−/− group. Finally, we proved that Abcg2 also affects pCS secretion into milk, with a more than 3-fold higher accumulation in milk and almost 6-fold higher milk-to-plasma ratio of wild-type versus Abcg2−/− mice. Overall, our results disclose that Abcg2 significantly affects plasma levels, biodistribution and milk secretion of pCS, thereby modulating its biological activity.