title: Role of ABCG2 in transport of the mammalian lignan enterolactone and its secretion into milk in Abcg2 knockout mice.
abstract: Lignans are phytoestrogens that are metabolized by the gut microbiota to enterodiol and enterolactone, the main biologically active enterolignans. Substantial interindividual variation in plasma concentration and urinary excretion of enterolignans has been reported, this being determined, at least in part, by the intake of lignan precursors, the gut microbiota, and the host's phase 2 conjugating enzyme activity. However, the role of ATP-binding cassette (ABC) transporters in the transport and disposition of enterolactone has not been reported so far. Active transport assays using parental and Madin-Darby canine kidney epithelial cells transduced with murine and human ABCG2 showed a significant increase in apically directed translocation of enterolactone in transduced cells, which was confirmed by using the selective ABCG2 inhibitor Ko143. In addition, enterolactone also inhibited transport of the antineoplastic agent mitoxantrone as a model substrate, with inhibition percentages of almost 40% at 200 μM for human ABCG2. Furthermore, the endogenous levels in plasma and milk of enterolactone in wild-type and Abcg2((-/-)) knockout female mice were analyzed. The milk/plasma ratio decreased significantly in the Abcg2((-/-)) phenotype, as compared with the wild-type mouse group (0.4 ± 0.1 as against 6.4 ± 2.6). This paper is the first to report that enterolactone is a transported substrate and therefore most probably a competitive inhibitor of ABCG2, which suggests it has a role in the interindividual variations in the disposition of enterolactone and its secretion into milk. The inhibitory activity identified provides a solid basis for further investigation in possible food-drug interactions.
authors.affiliation: Department of Biomedical Sciences, Physiology, Veterinary Faculty (V.M., A.I.A., J.A.O., G.M.) and Instituto de Desarrollo Ganadero y Sanidad Animal (J.A.O., G.M.), University of Leon, Leon, Spain; and Research Group on Quality, Safety, and Bioactivity of Plant Foods, Centro de Edafología y Biología Aplicada del Segura, Murcia, Spain (R.G.-V., F.T.-B., J.C.E.).
authors.forename: Verónica
authors.initials: V
authors.lastname: Miguel
authors.forename: Jon Andoni
authors.initials: JA
authors.lastname: Otero
authors.forename: Rocío
authors.initials: R
authors.lastname: García-Villalba
authors.forename: Francisco
authors.initials: F
authors.lastname: Tomás-Barberán
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Espín
authors.forename: Gracia
authors.initials: G
authors.lastname: Merino
authors.forename: Ana I
authors.initials: AI
authors.lastname: Álvarez
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport; D054659:Diketopiperazines; D004285:Dogs; D005260:Female; D006576:Heterocyclic Compounds, 4 or More Rings; D017705:Lignans / Q000097:blood / Q000493:pharmacokinetics*; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D018345:Mice, Knockout; D008892:Milk / Q000737:chemistry*; D008942:Mitoxantrone / Q000378:metabolism / Q000493:pharmacokinetics; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D013379:Substrate Specificity
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; C501412:Abcg2 protein, mouse; D054659:Diketopiperazines; D006576:Heterocyclic Compounds, 4 or More Rings; D017705:Lignans; D009363:Neoplasm Proteins; D008942:Mitoxantrone; D000241:Adenosine; D015107:4-Butyrolactone; C029497:2,3-bis(3'-hydroxybenzyl)butyrolactone