Genetic and Dietary Regulation of Glyburide Efflux by the Human Placental Breast Cancer Resistance Protein Transporter
| Autor: | Barry Weinberger, Poi Yu Sofia Yuen, Ludwik Gorczyca, Lauren M. Aleksunes, Vivek Gupta, Kristin M. Bircsak, Anna M. Vetrano |
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| Rok vydání: | 2016 |
| Předmět: |
Adult
0301 basic medicine medicine.medical_specialty Adolescent Abcg2 Placenta Estrogen receptor Genistein Phytoestrogens Biology Pharmacology Binding Competitive Metabolism Transport and Pharmacogenomics Young Adult 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Downregulation and upregulation Pregnancy Internal medicine Glyburide medicine ATP Binding Cassette Transporter Subfamily G Member 2 Humans Hypoglycemic Agents Receptor L-Lactate Dehydrogenase HEK 293 cells Transfection Diet Neoplasm Proteins HEK293 Cells 030104 developmental biology Endocrinology Receptors Estrogen chemistry 030220 oncology & carcinogenesis embryonic structures biology.protein Molecular Medicine ATP-Binding Cassette Transporters Female |
| Zdroj: | Journal of Pharmacology and Experimental Therapeutics. 357:103-113 |
| ISSN: | 1521-0103 |
| Popis: | Glyburide is frequently used to treat gestational diabetes owing to its low fetal accumulation resulting from placental efflux by the breast cancer resistance protein (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 (3)H-glyburide in both wild-type (WT) and C421A-BCRP HEK-expressing cells, with greater accumulation of (3)H-glyburide in cells expressing the C421A variant. In BeWo cells, exposure to genistein for 60 minutes increased the accumulation of (3)H-glyburide 30%-70% at concentrations relevant to dietary exposure (IC50 ∼180 nM). Continuous exposure of BeWo cells to genistein for 48 hours reduced the expression of BCRP mRNA and protein by up to 40%, which impaired BCRP transport activity. Pharmacologic 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 hours did not alter BCRP protein expression in explants dissected from healthy term placentas. These data suggest that whereas genistein can act as a competitive inhibitor of BCRP-mediated transport, its ability to downregulate 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. |
| Databáze: | OpenAIRE |
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