Abstract
Glyburide is frequently used to treat gestational diabetes due to its low fetal accumulation resulting from placental efflux by the BCRP/ABCG2 transporter. Here we sought to determine how exposure to the dietary phytoestrogen genistein and expression of a loss-of-function polymorphism in the ABCG2 gene (C421A) impacted the transport of glyburide by BCRP using stably-transfected human embryonic kidney 293 (HEK) cells, human placental choriocarcinoma BeWo cells and human placental explants. Genistein competitively inhibited the BCRP-mediated transport of 3H-glyburide in both wild-type (WT) and C421A-BCRP HEK-expressing cells, with greater accumulation of 3H-glyburide in cells expressing the C421A variant. In BeWo cells, exposure to genistein for 60 min increased the accumulation of 3H-glyburide 30-70% at concentrations relevant to dietary exposure (IC50 ~180 nM). Continuous exposure of BeWo cells to genistein for 48 h reduced the expression of BCRP mRNA and protein by up to 40%, which impaired BCRP transport activity. Pharmacological antagonism of the estrogen receptor attenuated the genistein-mediated downregulation of BCRP expression, suggesting that phytoestrogens may reduce BCRP levels through this hormone receptor pathway in BeWo cells. Interestingly, genistein treatment for 48 h did not alter BCRP protein expression in explants dissected from healthy term placentas. These data suggest that while genistein can act as a competitive inhibitor of BCRP-mediated transport, its ability to down-regulate placental BCRP expression may only occur in choriocarcinoma cells. Overall, this research provides important mechanistic data regarding how the environment (dietary genistein) and a frequent genetic variant (ABCG2, C421A) may alter the maternal-fetal disposition of glyburide.
- The American Society for Pharmacology and Experimental Therapeutics