title: Genetic and Dietary Regulation of Glyburide Efflux by the Human Placental Breast Cancer Resistance Protein Transporter.
abstract: 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.
authors: Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy (K.M.B., L.M.A., L.G.), and Environmental and Occupational Health Sciences Institute, Rutgers, The State University of New Jersey (L.M.A.), Piscataway, New Jersey; Departments of Obstetrics and Gynecology (V.G.) and Pediatrics (P.Y.S.Y., A.M.V.), Rutgers University Robert Wood Johnson Medical School, New Brunswick, New Jersey; Hofstra North Shore-LIJ School of Medicine, Cohen Children's Medical Center of New York, New Hyde Park, New York (B.I.W.).
authors: Kristin M
authors: KM
authors: Bircsak
authors: Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy (K.M.B., L.M.A., L.G.), and Environmental and Occupational Health Sciences Institute, Rutgers, The State University of New Jersey (L.M.A.), Piscataway, New Jersey; Departments of Obstetrics and Gynecology (V.G.) and Pediatrics (P.Y.S.Y., A.M.V.), Rutgers University Robert Wood Johnson Medical School, New Brunswick, New Jersey; Hofstra North Shore-LIJ School of Medicine, Cohen Children's Medical Center of New York, New Hyde Park, New York (B.I.W.).
authors: Vivek
authors: V
authors: Gupta
authors: Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy (K.M.B., L.M.A., L.G.), and Environmental and Occupational Health Sciences Institute, Rutgers, The State University of New Jersey (L.M.A.), Piscataway, New Jersey; Departments of Obstetrics and Gynecology (V.G.) and Pediatrics (P.Y.S.Y., A.M.V.), Rutgers University Robert Wood Johnson Medical School, New Brunswick, New Jersey; Hofstra North Shore-LIJ School of Medicine, Cohen Children's Medical Center of New York, New Hyde Park, New York (B.I.W.).
authors: Poi Yu Sofia
authors: PY
authors: Yuen
authors: Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy (K.M.B., L.M.A., L.G.), and Environmental and Occupational Health Sciences Institute, Rutgers, The State University of New Jersey (L.M.A.), Piscataway, New Jersey; Departments of Obstetrics and Gynecology (V.G.) and Pediatrics (P.Y.S.Y., A.M.V.), Rutgers University Robert Wood Johnson Medical School, New Brunswick, New Jersey; Hofstra North Shore-LIJ School of Medicine, Cohen Children's Medical Center of New York, New Hyde Park, New York (B.I.W.).
authors: Ludwik
authors: L
authors: Gorczyca
authors: Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy (K.M.B., L.M.A., L.G.), and Environmental and Occupational Health Sciences Institute, Rutgers, The State University of New Jersey (L.M.A.), Piscataway, New Jersey; Departments of Obstetrics and Gynecology (V.G.) and Pediatrics (P.Y.S.Y., A.M.V.), Rutgers University Robert Wood Johnson Medical School, New Brunswick, New Jersey; Hofstra North Shore-LIJ School of Medicine, Cohen Children's Medical Center of New York, New Hyde Park, New York (B.I.W.).
authors: Barry I
authors: BI
authors: Weinberger
authors: Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy (K.M.B., L.M.A., L.G.), and Environmental and Occupational Health Sciences Institute, Rutgers, The State University of New Jersey (L.M.A.), Piscataway, New Jersey; Departments of Obstetrics and Gynecology (V.G.) and Pediatrics (P.Y.S.Y., A.M.V.), Rutgers University Robert Wood Johnson Medical School, New Brunswick, New Jersey; Hofstra North Shore-LIJ School of Medicine, Cohen Children's Medical Center of New York, New Hyde Park, New York (B.I.W.).
authors: Anna M
authors: AM
authors: Vetrano
authors: Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy (K.M.B., L.M.A., L.G.), and Environmental and Occupational Health Sciences Institute, Rutgers, The State University of New Jersey (L.M.A.), Piscataway, New Jersey; Departments of Obstetrics and Gynecology (V.G.) and Pediatrics (P.Y.S.Y., A.M.V.), Rutgers University Robert Wood Johnson Medical School, New Brunswick, New Jersey; Hofstra North Shore-LIJ School of Medicine, Cohen Children's Medical Center of New York, New Hyde Park, New York (B.I.W.) aleksunes@eohsi.rutgers.edu.
authors: Lauren M
authors: LM
authors: Aleksunes
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D000293:Adolescent; D000328:Adult; D001667:Binding, Competitive / Q000187:drug effects; D004032:Diet; D005260:Female; D019833:Genistein / Q000378:metabolism / Q000494:pharmacology; D005905:Glyburide / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000378:metabolism*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D048789:Phytoestrogens / Q000378:metabolism / Q000494:pharmacology; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors; D055815:Young Adult
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D007004:Hypoglycemic Agents; D009363:Neoplasm Proteins; D048789:Phytoestrogens; D011960:Receptors, Estrogen; D019833:Genistein; D007770:L-Lactate Dehydrogenase; D005905:Glyburide