Modulation of endocrine and transport functions in human trophoblasts by saquinavir and nelfinavir Delphine Beghin a, *, Franc ¸ois Forestier a , Marie-Sophie Noe ¨ l-Hudson a , Laurent Gavard a,b , Jean Guibourdenche c , Robert Farinotti a,d , Sophie Gil a a Univ Paris-Sud, EA 2706, IFR141, Faculte ´ de Pharmacie, Chaˆtenay- Malabry, France b Hoˆpital Louis Mourier, Service de Gyne ´cologie-Obste ´trique, Colombes, France c Universite ´ Rene ´ Descartes Paris V, Inserm UMR767, Faculte ´ de Pharmacie, Paris, France d Service de Pharmacie, Groupe hospitalier Pitie ´-Salpeˆtrie `re, Assistance Publique-Hoˆpitaux de Paris, Paris, France 1. Introduction The placenta assumes various functions during pregnancy allowing respiratory exchanges, transfer of nutrients between maternal and fetal circulations, and providing hormones which are essential for fetal development. Mononucleated villous cytotro- phoblasts aggregate and fuse to form a multinucleated syncytio- trophoblast, which is at the interface between the mother and the fetus. The syncytiotrophoblast will then represent the endocrine tissue of the placenta, secreting large amounts of hormones including human chorionic gonadotropin hormone (hCG) [1]. Although the placenta has been viewed as a protective barrier, the transfer of drugs administered to the mother during pregnancy is now widely demonstrated [2]. AIDS represents a major public health problem. To limit the transmission of HIV between the mother and the fetus, it is necessary to effectively treat the former while ensuring the safety of the latter [3,4]. Treatment usually consists of a combination of non-nucleoside and nucleoside reverse transcriptase inhibitors (NNRTIs and NRTIs) and at least one protease inhibitor (PI). Available data regarding placental transfer of protease inhibitors (PIs) suggest that there are variations between PIs. Concentrations of saquinavir were found to be extremely low in fetuses compared to their mothers while concentrations of nelfinavir were higher [5]. Transport proteins have an important role in regulating the distribution across the maternal–fetal interface [6]. Among these transporters, P-glycoprotein (P-gp, ABCB1) encoded by the ABCB1 gene is one of the most extensively studied and best characterized ATP-dependent drug efflux transporter in the placenta [7,8]. P-gp, expressed on the border of the syncytiotrophoblast microvilli, participates in efflux of hydrophobic and cationic drugs into the maternal blood, thereby reducing fetal exposure to chemicals [9]. These results have been reported in animal and in vitro models showing that abcb1 gene knockout mice lacking placental P-gp have an increased fetal susceptibility to avermectin-induced teratogenicity [10], and that P-gp extrudes xenobiotics backwards into the maternal compartment [11–13]. Caveolae are known to be involved in several cellular processes including signal transduc- tion, cholesterol transport and endocytosis [14]. Caveolin-1 is a major caveolar coat protein that has the ability to engage in European Journal of Obstetrics & Gynecology and Reproductive Biology 152 (2010) 55–59 ARTICLE INFO Article history: Received 28 October 2009 Received in revised form 19 March 2010 Accepted 24 May 2010 Keywords: P-glycoprotein Trophoblast cells Placenta hCG Saquinavir Nelfinavir Caveolin-1 ABSTRACT Objectives: The distribution of drugs to the maternal–fetal interface is influenced by the expression of various efflux transporters. Among these transporters, P-glycoprotein (P-gp) is responsible for the efflux of a great number of drugs such as protease inhibitors of the human immunodeficiency virus, thus reducing the chemical exposure of the fetus. Study design: The effects of saquinavir and nelfinavir were evaluated on human trophoblast functions and integrity by investigating their effect on human chorionic gonadotropin (hCG) secretion and on P-gp expression and functionality. Results: Nelfinavir significantly reduced hCG secretion by 30% after a 48-h treatment but it had no effect on syncytia formation. Saquinavir had no effect on hCG secretion but significantly increased both expression (to a 2-fold extent) and functionality (by 17.9%) of P-gp, whereas nelfinavir only increased functionality (by 23.1%) with a dissociation of P-gp from caveolin-1. Conclusion: These results suggest that the effects of saquinavir and nelfinavir differ on trophoblast functions. ß 2010 Elsevier Ireland Ltd. All rights reserved. * Corresponding author at: Faculte ´ de Pharmacie – UPRES EA 2706, Laboratoire de Pharmacie Clinique, 5 rue jean baptiste Cle ´ ment, 92296 Cha ˆtenay-Malabry cedex, France. Tel.: +33 1 4683 5577; fax: +33 1 4683 5618. E-mail addresses: delphinebeghin@free.fr, d.beghin@infonie.fr (D. Beghin). Contents lists available at ScienceDirect European Journal of Obstetrics & Gynecology and Reproductive Biology journal homepage: www.elsevier.com/locate/ejogrb 0301-2115/$ – see front matter ß 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ejogrb.2010.05.023