An altered tissue distribution of flaxseed lignans and their metabolites in Abcg2 knockout mice.

Key Points

The human Breast Cancer Resistance Protein (BCRP/ABCG2) is a membrane transporter (named Abcg2 in mice). It is an efflux protein with an important capacity to limit the bioavailability  of multiple compounds. Previous studies have reported that flax lignans ENL, END and SECO are in vitro substrates of murine Abcg2 and human ABCG2 in transepithelial transport experiments using MDCKII cells. In this study, END inhibited 5α-reductase that catalyzes the conversion of testosterone into 5α-dihydrotestosterone, the most active androgen; which could explain the health benefits of flaxseed in a rat model of benign prostatic hypertrophy. In addition, the cancer cell proliferation biomarker Ki67 decreased in prostatecancer patients after supplementation of a flaxseed-rich diet for 30 days. Enterolignans have also been reported to
increase plasma androstanediol glucuronide in men through interactions with polymorphisms in the CYP19 gene. In this study, END was the most abundant enterolignan found in testes. The cancer lowering potential of lignans may be due in part to their impact on Abcg2.

ABSTRACT

Lignans are dietary polyphenols, which are metabolized by gut microbiota into the phytoestrogenic metabolites enterolignans, mainly enterolactone and enterodiol. Breast Cancer Resistance Protein (BCRP/ABCG2) is an efflux transporter that affects the plasma and milk secretion of several drugs and natural compounds. We hypothesized here that Abcg2 could influence the levels of lignans and their derived metabolites in target tissues. Consequently, we aimed to evaluate the role of Abcg2 in the tissue distribution of these compounds. We used Abcg2-/- knockout and wild-type male mice fed with a lignan-enriched diet for one week and analysed their plasma, small intestine, colon, liver, kidneys and testicles. High levels of lignans as well as enterolignans and their glucuronide and sulfate conjugates in the small intestine and colon were detected, with higher concentrations of the conjugates in the wild-type compared with Abcg2-/- mice. Particularly relevant was the detection of 24-fold and 8-fold higher concentrations of enterolactone-sulfate and enterolactone-glucuronide, respectively, in the kidney of Abcg2-/- compared with wild-type mice. In conclusion, our study showed that lignans and their derived metabolites were in vivo substrates of Abcg2, which affected their plasma and tissue levels. These results highlight the role of Abcg2 in influencing the health-beneficial properties of dietary lignans.