Genistein Reduces Glyburide Efflux by the Human Placental BCRP Transporter: Transcriptional Regulation and Direct Inhibition

Abstract

The hypoglycemic drug glyburide is routinely used in the treatment of gestational diabetes. Fetal exposure to glyburide is typically low because the BCRP/ABCG2 transporter on placental syncytiotrophoblasts prevents its maternal‐to‐fetal transfer. The purpose of this study was to determine the effect of the dietary soy isoflavone genistein on the transcriptional regulation and direct inhibition of BCRP. For the regulation studies, human choriocarcinoma BeWo placental cells were incubated with genistein (0‐10 µM). After 48 h exposure to genistein, placental BeWo cells exhibited a 40% reduction in BCRP mRNA and protein. Down‐regulation of BCRP led to a 50% increase in the accumulation of the BCRP substrate, Hoechst 33342 in BeWo cells treated with genistein. Further, down‐regulation of BCRP by genistein was prevented by removal of serum from the media. In addition to modulating the expression of BCRP, genistein also competitively inhibited its transport in HEK cells overexpressing the wild‐type (WT) or functionally‐reduced BCRP variant (C421A). As expected, C421A‐BCRP cells had 10% greater accumulation of 3H‐glyburide than WT‐BCRP cells. Genistein increased the accumulation of 3H‐glyburide in both WT‐ and C421A‐BCRP cells by 50%. Taken together, pregnant women expressing the common loss‐of‐function C421A‐BCRP variant and/or consume genistein through a soy diet may be at an elevated risk for fetal exposure to glyburide and subsequent neonatal hypoglycemia. Support: ES020522, ES005022, ES007148, AFPE and PhRMA Predoctoral Fellowships.