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.
Footnotes
- Received November 11, 2013.
- Accepted February 25, 2014.
This work was supported by the Spanish Ministry of Economy and Competitiveness and the European Regional Development Fund [Projects CICYT AGL2012-31116, AGL2011-22447] and the Seneca Foundation of the Murcia Region, Spain [Excellence Group GERM 06 04486, 05556/PI/04, Consolider Ingenio 2010, CSD2007-00063 (Fun-C-Food)].
J.A.O. holds a predoctoral fellowship of the Basque Government and R.G.-V. is the holder of a JAE-DOC contract from the Spanish Higher Council for Scientific Research, cofinanced by the European Social Fund.
- Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
DMD articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|