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The gut microbiota ellagic acid-derived metabolite urolithin A, and its sulfate conjugate, are substrates for the drug efflux transporter breast cancer resistance protein (ABCG2/BCRP).

J Agric Food Chem. 2013 Apr 15;

Authors: González-Sarrías A, Miguel V, Merino G, Lucas R, Morales JC, Tomás-Barberán F, Alvarez AI, Espín JC


The breast cancer resistance protein (BCRP/ABCG2) is a drug efflux transporter that can affect the pharmacological and toxicological properties of many molecules. Urolithins, metabolites produced by the gut microbiota from ellagic acid (EA) and ellagitannins, have been acknowledged with in vivo anti-inflammatory and cancer chemopreventive properties. We here evaluated whether urolithins (Uro-A, -B, -C and -D), their main phase II metabolites Uro-A sulfate, Uro-A glucuronide, and Uro-B glucuronide as well as their precursor EA were substrates for ABCG2/BCRP. Parental and Bcrp1-transduced MDCKII cells were used for active transport assays. Uro-A, and in a lesser extent Uro-A sulfate, showed a significant increase in apically directed translocation in Bcrp1-transduced cells. Bcrp1 did not show affinity for the rest of tested compounds. Data were confirmed for murine, human, bovine and ovine BCRP-transduced subclones as well as with the use of the selective BCRP inhibitor Ko143. The transport inhibition by Uro-A was analyzed by flow cytometry compared to Ko143 using the antineoplastic agent mitoxantrone as a model substrate. Results showed that Uro-A was able to inhibit mitoxantrone transport in a dose-dependent manner. We report here for the first time that Uro-A and its sulfate conjugate are ABCG2/BCRP substrates. Our results suggest that physiologically relevant concentrations of these gut microbiota-derived metabolites could modulate ABCG2/BCRP-mediated transport processes and mechanisms of cancer drug resistance. Further in vivo investigations are warranted.

PMID: 23586460 [PubMed - as supplied by publisher]