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 ( p CS), a well-known uremic toxin, is the main metabolite of p -Cresol ( p C), produced from dietary aromatic amino acids by gut microbiota. We aimed to characterize the in vitro and in vivo interaction of p CS with the ABCG2 transporter. Using MDCK–II cells overexpressing the transporter, we found that p CS is an in vitro substrate of ABCG2. Furthermore, using wild-type and Abcg2 −/− mice, we showed that plasma AUC 0−240 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 p CS levels versus the wild-type group. Moreover, p CS 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 p CS 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 p CS, thereby modulating its biological activity.
Millán-García et al. (Sat,) studied this question.