The Journal is included in Russian and International Library and Abstract Databases
Russain Science Index (Russia)
DOI Registration Agency (USA)

Вirth defects: the role of P-glycoprotein


T. Pikuzа1; Professor R. Chilova(1), MD; E. Sоkоvа1, 2, Candidate of Medical Sciences; R.
Kazakov(1), Candidate of Biological Sciences; K. Akopov(3); O. Astsaturova(1), Candidate of Medical Sciences
(1)I.M. Sechenov First Moscow State Medical University (Sechenov University) (2)Scientific Centre for Expert
Evaluation of Medicinal Products, Moscow (3)State Clinical Hospital named. S.S. Yudina, Moscow

ABC transporters and mainly P-glycoprotein play critical physiological and protective roles in during reproductive processes. The P-glycoprotein, encoded by the ABCB1 gene, is suggested to protect the developing embryo from drugs which are substrates of P-glycoprotein and other xenobiotic exposures. It is increasingly recognized that the activity of these transporters is affected by genetic polymorphisms. The article looks into the recent studies exploring the association between P-glycoprotein polymorphisms and the risk of fetal birth defects associated with medication use during pregnancy.

obstetrics and gynecology
birth defects
drug transporters

  1. Oza S., Lawn J.E., Hogan D.R. et al. Neonatal cause-of-death estimates for the early and late neonatal periods for 194 countries: 2000–2013. Bull World Health Organ. 2015; 93 (1): 19–28. DOI: 10.2471/BLT.14.139790
  2. United Nations Inter-agency Group for Child Mortality Estimation (UN IGME). Levels & Trends in Child Mortality. New York: UNICEF, 2017.
  3. Demikova N.S., Lapina A.S. Vrozhdennye poroki razvitija v regionah Rossijskoj Federatsii (itogi monitoringa za 2000–2010 gg.). Ros vestn perinatol i pediatr. 2012; 57 (2): 91–8 [Demikova N.S., Lapina A.S. Congenital malformations in the regions of the Russian Federation (results of monitoring for 2000–2010). Ros vestn perinatol i pediatr (Russian Bulletin of Perinatology and Pediatrics). 2012; 57 (2): 91–8 (in Russ.)].
  4. Feldkamp M.L., Carey J.C., Byrne J.L.B. et al. Etiology and clinical presentation of birth defects: population based study. BMJ. 2017; 357. DOI: 10.1136/bmj.j2249
  5. Holmes L.B., Westgate M.-N., Toufaily M.H. Malformations attributed to the process of vascular disruption. Birth Defects Res. 2018; 110: 98–107. DOI: 10.1002/bdr2.1160
  6. Toufaily MH, Westgate Marie-Noel, Lin AE, et al. Research Article Causes of Congenital Malformations. Birth Defects Research. 2018; 110: 87–91. DOI: 10.1002/bdr2.1105
  7. Tomson T., Battino D., Bonizzoni E. et al. Comparative risk of major congenital malformations with eight different antiepileptic drugs: a prospective cohort study of the EURAP registry. Lancet Neurol. 2018; 17: 530–8. DOI: 10.1016/S1474-4422(18)30107-8
  8. Klausner R., Shapiro E.D., Elder R.W. Evaluation of a Screening Program to Detect Critical Congenital Heart Defects in Newborns. Hosp Pediatr. 2017; 7(4): 214–218. DOI: 10.1542/hpeds.2016-0176
  9. EUROCAT – European Surveillance of Congenital Anomalies. Publication of the EUROCAT statistical monitoring report and updated prevalence tables. Available from: (last accessed: 21 September 2016).
  10. Zhu H., Kartiko S., Finnell R.H. Importance of gene - environment interactions in the etiology of selected birth defects. Clin Genet. 2009; 75 (5): 409–23. DOI: 10.1111/j.1399-0004.2009.01174.x
  11. Atkinson D., Brice-Bennet S., D’souza S.W. Antiepileptic Medication During Pregnancy: Does Fetal Genotype Affect Outcome? Pediatric research. 2007; 62 (2): 120–7. DOI: 10.1203/PDR.0b013e3180a02e50
  12. Guideline on the exposure to medicinal products during pregnancy: need for post authorisation. EMEA/CHMP/313666/2005, London, 14 November, 2005.
  13. Personalizirovannaja meditsina: kliniko-farmakologicheskie aspekty. Pod red. V.G. Kukesa. M.: Izdatel'stvo AGO Mezhdunarodnaja assotsiatsija klinicheskih farmakologov i farmatsevtov, 2014; 260 s. [Personalizirovannaya meditsina: kliniko-farmakologicheskie aspekty. Pod red. V.G. Kukesa. M.: Izdatel’stvo AGO Mezhdunarodnaya assotsiatsiya klinicheskikh farmakologov i farmatsevtov, 2014; 260 s. (in Russ.)].
  14. Kukes V.G., Sokova E.A., Ignat'ev I.V. i dr. Glikoprotein R i zdorov'e ploda. Problemy reproduktsii. 2010; 5: 78–84 [Kukes V.G., Sokova E.A., Ignat’ev I.V. et al. Glycoprotein P and fetal condition. Problemy reproduktsii. 2010; 5: 78–84 (in Russ.)].
  15. Daud A.N.A., Bergman J.E.H., Kerstjens-Frederikse W.S. et al. Prenatal exposure to serotonin reuptake inhibitors and congenital heart anomalies: an exploratory pharmacogenetics study. Pharmacogenomics. 2017; 18 (10): 987–1001. DOI: 10.2217/pgs-2017-0036
  16. Bloise E., Ortiga-Carvalho T.M., Reis F.M. et al. ATP-binding cassette transporters in reproduction: a new frontier. Hum Reprod Update. 2016; 22: 164–81. DOI: 10.1093/humupd/dmv049
  17. Brayboy L.M., Oulhen N., Long S. et al. Multidrug resistance transporter-1 and breast cancer resistance protein protect against ovarian toxicity, and are essential in ovarian physiology. Reprod Toxicol. 2017; 69: 121–31. DOI: 10.1016/j.reprotox.2017.02.002
  18. Brayboy L.M., Knapik L.O., Long S. et al. Ovarian hormones modulate multidrug resistance transporters in the ovary. Contraception and Reproductive Medicine. 2018; 3: 26. DOI: 10.1186/s40834-018-0076-7
  19. Helguera G., Eghbali M., Sforza D. et al. Changes in global gene expression in rat myometrium in transition from late pregnancy to parturition. Physiol Genomics. 2009; 36: 89–97. DOI: 10.1152/physiolgenomics.00290.2007
  20. Bloise E., Feuer S.K., Rinaudo P.F. Comparative intrauterine development and placental function of ART concepti: implications for human reproductive medicine and animal breeding. Hum Reprod Update. 2014; 20: 822–39. DOI: 10.1093/humupd/dmu032
  21. Bleier B.S., Nocera A.L., Iqbal H. et al. P-glycoprotein functions as an immunomodulator in healthy human primary nasal epithelial cells. Int Forum Allergy Rhinol. 2013; 3 (6): 433–8. DOI: 10.1002/alr.21166
  22. Iqbal M, Audette MC, Petropoulos S, et al. Placental drug transporters and their role in fetal protection. Placenta. 2012; 33: 137–42. DOI: 10.1016/j.placenta.2012.01.008
  23. Sawicki W.T., Kujawa M., Jankowska-Steifer E. et al. Temporal/spatial expression and efflux activity of ABC transporter, P-glycoprotein/Abcb1 isoforms and Bcrp/Abcg2 during early murine development. Gene Expr Patterns. 2006; 6: 738–46. DOI: 10.1016/j.modgep.2005.12.003
  24. Joshi A.A., Vaidya S.S., St-Pierre M.V. et al. Placental ABC Transporters: Biological Impact and Pharmaceutical Significance. Pharm Res. 2016; 33 (12): 2847–78. DOI: 10.1007/s11095-016-2028-8
  25. Koren Gideon, Ornoy Asher. The role of the placenta in drug transport and fetal drug exposure. Expert Review of Clinical Pharmacology. 2018; 11 (4): 373–85. DOI: 10.1080/17512433.2018
  26. Han L.W., Gao C., Mao Q. An update on expression and function of P-gp/ABCB1 and BCRP/ABCG2 in the placenta and fetus. Exp Opin Drug Metabol Toxicol. 2018; 14 (8): 817–29. DOI: 10.1080/17425255.2018.1499726
  27. Sharom F.J. Complex interplay between the P-glycoprotein multidrug efflux pump and the membrane: its role in modulating protein function. Front Oncol. 2014; 4: 41. DOI: 10.3389/fonc.2014.00041
  28. Lye R., Bloise E., Nadeem L, et al. Glucocorticoids modulate multidrug resistance transporters in the first trimester human placenta. Cell Mol Med. 2018; 22 (7): 3652–60. DOI: 10.1111/jcmm.13646
  29. Marzolini C., Rudin C., Decosterd L.A. et al. Transplacental passage of protease inhibitors at delivery. Aids. 2002; 16 (6): 889–93. DOI: 10.1097/00002030-200204120-00008
  30. Imperio G.E., Javam M., Lye R. et al. Gestational age-dependent gene expression profiling of ATP-binding cassette transporters in the healthy human placenta. J Cell Mol Med. 2019; 23: 610–8. DOI: 10.1111/jcmm.13966
  31. Bruhn O., Cascorbi I. Polymorphisms of the drug transporters ABCB1, ABCG2, ABCC2 and ABCC3 and their impact on drug bioavailability and clinical relevance. Exp Opin Drug Metab Toxicol. 2014; 10 (10): 1337–54. DOI: 10.1517/17425255.2014.952630
  32. Hitzl M., Schaeffeler E., Hocher B. et al. Variable expression of P-glycoprotein in the human placenta and its association with mutations of the multidrug resistance 1 gene (MDR1, ABCB1). Pharmacogenetics. 2004; 14: 309–18. DOI: 10.1097/00008571-200405000-00006
  33. Obermann-Borst S.A., Isaacs A., Younes Z. et al. General maternal medication use, folic acid, the MDR1 C3435T polymorphism, and the risk of a child with a congenital heart defect. Am J Obstet Gynecol. 2011; 204 (3): 236.e1–8. DOI: 10.1016/j.ajog.2010.10.911
  34. Frigerio B., Bizzoni C., Jansen G. et al. Folate receptors and transporters: biological role and diagnostic/therapeutic targets in cancer and other diseases. J Exp Clin Cancer Res. 2019; 38 (1): 125. DOI: 10.1186/s13046-019-1123-1
  35. Lankas G.R., Wise L.D., Cartwright M.E. et al. Placental P-glycoprotein deficiency enhances susceptibility to chemically induced birth defects in mice. Reprod Toxicol. 1998; 12 (4): 457–63. DOI: 10.1016/S0890-6238(98)00027-6
  36. Smit J.W., Huisman M.T., van Tellingen O. et al. Absence or pharmacological blocking of placental P-glycoprotein profoundly increases fetal drug exposure. J Clin Invest. 1999; 104 (10): 1441–7. DOI: 10.1172/JCI7963
  37. Staud F., Cerveny L., Ceckova M. Pharmacotherapy in pregnancy: effect of ABC and SLC transporters on drug transport across the placenta and fetal drug exposure. J Drug Target. 2012; 20: 736–63. DOI: 10.3109/1061186X.2012.716847
  38. Daud A.N.A., Bergman J.E.H., Bakker M.K. et al. Pharmacogenetics of drug-induced birth defects: The role of polymorphisms of placental transporter proteins. Pharmacogenomics. 2014; 15 (7): 1029–41. DOI: 10.2217/pgs.14.62
  39. Bliek B.J., van Schaik R.H.N., van der Heiden I.P. et al. Maternal medication use, carriership of the ABCB1 3435C > T polymorphism and the risk of a child with cleft lip with or without cleft palate. Am J Med Genet A. 2009; 149A (10): 2088–92. DOI: 10.1002/ajmg.a.33036
  40. Martinelli M., Carinci F., Morselli P.G. et al. Study of ABCB1 multidrug resistance protein in a common orofacial malformation. Int J Immunopathol Pharmacol. 2011; 24: 1–5. DOI: 10.1177/03946320110240S201
  41. Wang C., Zhou K., Xie L. et al. Maternal Medication Use, Fetal 3435 C>T Polymorphism of the ABCB1 Gene, and Risk of Isolated Septal Defects in a Han Chinese Population. Pediatr Cardiol. 2014; 35 (7): 1132–41. DOI: 10.1371/journal.pone.0068807
  42. Omoumi A., Wang Z., Yeow V. et al. Fetal polymorphisms at the ABCB1-transporter gene locus are associated with susceptibility to non-syndromic oral cleft malformations. Eur J Hum Genet. 2013; 21(12): 1436–41. DOI: 10.1038/ejhg.2013.25