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Functional role of P-glycoprotein in the human blood-placental barrier
Melissa Mölsä1, Tuija Heikkinen, Jukka Hakkola
1Department of Pharmacology and Clinical Pharmacology, University of Turku, Finland.
Insights
P-glycoprotein acts as a barrier in the human placenta, limiting drug transfer to the fetus. Blocking this protein increases fetal drug exposure, potentially causing harm.
Area of Science:
- Pharmacology
- Reproductive Biology
- Drug Metabolism
Background:
- P-glycoprotein (P-gp) is hypothesized to form a protective barrier in the placenta against xenobiotics.
- Understanding P-gp's role is crucial for assessing fetal drug exposure risks during pregnancy.
Purpose of the Study:
- To investigate the functional significance of P-glycoprotein in the human blood-placental barrier.
- To determine P-gp's role in maternal-to-fetal and fetal-to-maternal xenobiotic transfer.
Main Methods:
- Utilized a dually perfused human placenta model with saquinavir as a probe drug.
- Employed P-gp inhibitors (PSC833, GG918) to assess transfer changes.
- Analyzed ABCB1 gene polymorphism and P-gp expression in placental tissues.
Main Results:
- Saquinavir transfer was significantly higher from fetus to mother than mother to fetus.
- P-gp inhibition markedly increased saquinavir transfer from mother to fetus (7.9-fold with PSC833, 6.2-fold with GG918).
- PSC833 did not affect fetal-to-maternal saquinavir transfer; P-gp expression correlated with inhibition effects.
Conclusions:
- P-glycoprotein plays a critical role in the maternal-to-fetal blood-placental barrier, limiting xenobiotic transfer.
- Pharmacological blockade of P-gp can disrupt this barrier, increasing fetal exposure to drugs.
- This disruption highlights a potential mechanism for drug-induced teratogenicity.
Objective:
In vitro and animal experiments suggest that P-glycoprotein forms a functional barrier between maternal and fetal blood circulation in the placenta, thus protecting the fetus from exposure to xenobiotics during pregnancy. In this study we aimed to characterize the role of P-glycoprotein in the blood-placental barrier by use of dually perfused human placenta.
Methods:
Twenty-eight human placentas were obtained after delivery, and both the maternal side and the fetal side were perfused for 2 hours. Saquinavir was used as a probe drug for P-glycoprotein-dependent active transfer, and PSC833 (valspodar) or GG918 was used as an inhibitor of P-glycoprotein function in a maternal-to-fetal and fetal-to-maternal perfusion setting. Genotyping for ABCB1 (C3435T and G2677A/T) polymorphism and quantification of P-glycoprotein expression were done for each placenta.
Results:
The fetal-to-maternal transfer of saquinavir was 108-fold higher (P = .003) compared with transfer from the maternal to the fetal direction. Preperfusion with PSC833 increased the placental transfer of saquinavir by 7.9-fold (P < .001), and preperfusion with GG918 increased it by 6.2-fold (P < .001). The end-perfusion transfer (percentage) of saquinavir at 120 minutes was 11-fold (P < .001) and 6-fold (P < .001) higher in placentas preperfused with PSC833 and GG918, respectively, compared with control. However, PSC833 had no effect on the transfer of saquinavir from the fetal to the maternal direction (P = .79). P-glycoprotein expression was correlated with the PSC833-induced change in the saquinavir transfer (r = 0.75, P = .086). ABCB1 polymorphism did not affect the PSC833- or GG918-induced change in the saquinavir transfer.
Conclusions:
P-glycoprotein has a major functional role in the human blood-placental barrier but a negligible role in the removal of substances from the fetal circulation to maternal blood. Pharmacologic blockade of P-glycoprotein function can lead to disruption of the blood-placental barrier and increase the transfer of P-glycoprotein substrates to the fetal side by several-fold, which may be a noteworthy mechanism for teratogenicity.
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