title: 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).
abstract: 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. This study evaluated whether urolithins (Uro-A, -B, -C, and -D) and 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, to 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 the 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. This study reports for the first time that Uro-A and its sulfate conjugate are ABCG2/BCRP substrates. The 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.
authors.affiliation: Research Group on Quality, Safety and Bioactivity of Plant Foods, Department of Food Science and Technology, CEBAS-CSIC, Campus de Espinardo, Murcia, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: González-Sarrías
authors.forename: Verónica
authors.initials: V
authors.lastname: Miguel
authors.forename: Gracia
authors.initials: G
authors.lastname: Merino
authors.forename: Ricardo
authors.initials: R
authors.lastname: Lucas
authors.forename: Juan C
authors.initials: JC
authors.lastname: Morales
authors.forename: Francisco
authors.initials: F
authors.lastname: Tomás-Barberán
authors.forename: Ana I
authors.initials: AI
authors.lastname: Alvarez
authors.forename: Juan C
authors.initials: JC
authors.lastname: Espín
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics; D002417:Cattle; D045744:Cell Line, Tumor; D003374:Coumarins / Q000494:pharmacology*; D054659:Diketopiperazines; D004285:Dogs; D004610:Ellagic Acid / Q000378:metabolism*; D005260:Female; D020719:Glucuronides / Q000494:pharmacology; D006576:Heterocyclic Compounds, 4 or More Rings; D006801:Humans; D047348:Hydrolyzable Tannins / Q000378:metabolism; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D064307:Microbiota; D008942:Mitoxantrone / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D012756:Sheep; D013431:Sulfates / Q000378:metabolism
chemical_list: C541506:3-(6-isobutyl-9-methoxy-1,4-dioxo-1,2,3,4,6,7,12,12a-octahydropyrazino(1',2'-1,6)pyrido(3,4-b)indol-3-yl)propionic acid tert-butyl ester; C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D003374:Coumarins; D054659:Diketopiperazines; D020719:Glucuronides; D006576:Heterocyclic Compounds, 4 or More Rings; D047348:Hydrolyzable Tannins; D009363:Neoplasm Proteins; D013431:Sulfates; C026423:3,8-dihydroxy-6H-dibenzo(b,d)pyran-6-one; D004610:Ellagic Acid; D008942:Mitoxantrone; D000241:Adenosine