Functional role and regulation of permeability‐glycoprotein (P‐gp) in the fetal membrane during drug transportation

Abstract

Objective: Na + /H + exchange regulatory factor-1 (NHERF-1) is a class I PDZ (PSD95/Discs-large/ZO-1) binding protein involved in cell-surface expression and stabilization of transporter proteins, including permeability-glycoprotein (P-gp) in various cell types. P-gp, expressed in placental trophoblasts, is an efflux transporter protein that influences the pharmacokinetics of various drugs used during pregnancy. Previously we have reported that NHERF-1 regulates fetal membrane inflammation. However, the role of NHERF-1 in regulating P-gp in the fetal membrane during drug transportation remains unclear. This study determined the interplay between NHERF-1 and P-gp in human fetal membrane cells.Methods: Fetal membranes from normal, term cesareans were screened for P-gp by immunohistochemistry (IHC). Chorionic trophoblast (CTC), with the highest expression of P-gp among fetal membrane cells, was further used to test interactive properties between NHERF-1 and P-gp. BeWo (placental trophoblast cell line) cells were used as a control. Immunoprecipitation (IP) of CTC lysates using the P-gp antibody followed by western blot determined co-precipitation of NHERF-1. Silencing NHERF-1 using small interfering RNA further tested the relevance of NHERF-1 in P-gp expression and function in CTC and BeWo cells. NHERF-1 regulation of P-gp's efflux function (drug resistance) was further tested using the ENZO TM efflux dye kit.Results: Immunohistochemistry localized, and western blot confirmed P-gp in human fetal membranes, primarily in the CTC with limited expression in the amnion epithelial layer. P-gp expression in the membranes was similar to that seen in the placenta.IP data showed P-gp co-precipitating with NHERF1. Silencing of NHERF-1 resulted in significant drug resistance suggesting P-gp function mediated through NHERF1 in CTCs. Conclusion:Proinflammatory mediator NHERF-1 regulates P-gp and control drug transportation across the fetal membranes. Our data suggest a novel functional role for fetal membranes during pregnancy. Besides the placenta, fetal membranes may also

Testing of drugs using human feto-maternal interface organ-on-chips provide insights into pharmacokinetics and efficacy

“…61 The recent discovery of multiple drug transporter proteins and drug-metabolizing enzymes in fetal membranes prompted us to speculate that the fetal membrane–decidual interface along with the placenta may also transport drugs. 12,62 To overcome current limitations and to test the potential of a 2nd FMi' to transport drugs, we used two distinct models of the OOCs and tested statin drug transport kinetics, metabolism, and efficacy. Statins were used as a model drug for testing our devices based on our in vitro and in vivo experiences with this drug.…”

“…Our recent findings have shown the functionally active transporter proteins including phospho-glycoprotein-1, breast cancer receptor protein-1, and organic anion transporter proteins in fetal membranes. 12,13…”

Acute Histological Chorioamnionitis and Birth Weight in Pregnancies With Preterm Prelabor Rupture of Membranes: A Retrospective Cohort Study

“…This hypothesis suggests that placental changes leading to impaired fetal growth are associated with the development of the acute inflammation of the amnion rather than the fetal inflammatory response, as shown in this study. We cannot fully exclude a contribution of fetal membranes on the production of the chemotactic stimuli along with the placenta for the following reasons: i) transporter proteins in the fetal membranes along with nutritional transport system suggests that fetal membranes play an equal role to that of the placenta in drug and nutrients transports (Ganguly et al, 2021;Kammala et al, 2022); ii) endogenous activities in the fetal membranes on cellular level can generate danger signals (Menon and Peltier, 2020;Sheller-Miller and Menon, 2020;Shahin et al, 2021;Shepherd et al, 2021;Tantengco et al, 2021); iii) fetal membranes function can be independent of the placenta and placental involvement (Menon, 2016); iv) fetal growth restriction can increase apoptosis in the chorionic trophoblast cells of fetal membranes and expression of parathyroid-related protein expression in the fetal membranes (Curtis et al, 2000;Murthi et al, 2005); and v) fetal membranes are not the mere extension of the placenta and have their own identity, function and hence, their compromise alone without the placental involvement can be detrimental (Collins et al, 1993;Menon and Moore, 2020). Therefore, functions of fetal membranes might be impaired in pregnancies complicated by the alteration of fetal growth.…”

Endocrine-disrupting compounds and their impact on human placental function: evidence from placenta organ-on-chip studies

“…The length of the cell chambers ranges from 1000-7000 μm, and all chambers had a height of 250 μmin accordance with previously established dimensions in other devices 21,[36][37][38][39][40][41] as well as based on existing knowledge on the volumes and surface areas of these cell layers in histological and microscopic sections of the placenta. [42][43][44] The microchannels lie in between these structures interconnecting the chambers. The height of the microchannels (5 μm) closely approximates in vivo thickness of the villous membrane.…”