Recent studies in animal models have indicated that the multi-drug resistant (MDR) gene product, P-glycoprotein (Pgp), of the placenta has a significant role in reducing chemical exposure to the fetus and the incidence of birth defects. Pgp is an active, polyspecific membrane- bound transporter expressed in tumor and normal tissues, including the placenta. In humans, Pgp is localized to the syncytio- and cyto- trophoblasts and is expressed throughout pregnancy. However, Pgp's role in controlling the disposition of drugs and steroids between the fetal and maternal compartments is unknown.. The objective of this proposal is to characterize the Pgp efflux mechanism of the trophoblast with respect to expression and transporting xenobiotics (e.g., anti-cancer agents, phenobarbital, rifampicin) and steroids of pregnancy (e.g., progesterone) and its regulation by these substances.
Under Aim 1 o of this proposal we will elucidate (a) the mRNA and protein expression, and (b) the localization of MDR1 in the human trophoblast.
In Aim 2 we will determine (a) the functional significance and (b) the asymmetry of human trophoblast transport of selected xenobiotics and steroid hormones.
Aim 3 studies are directed at characterization of the regulatory mechanism(s) by which certain xenobiotics and steroid hormones control (a) the expression and (b) the function of MDR1 of the human trophoblast. We expect that at the conclusion of this proposal we will have established the role of Pgp and related mechanisms (e.g. breast cancer resistance protein) of the trophoblast in transporting substrates that include xenobiotics and the steroid hormones.. We also expect to establish a putative role and the biochemical mechanisms by which certain xenobiotics and steroid hormones modulate Pgp expression and/or function. Our long term goal is to develop a detailed understanding of the mechanisms controlling drugs and drugs of abuse distribution across the human detailed understanding of the mechanisms controlling drugs and drugs of abuse distribution across the human trophoblast and to identify appropriate in vitro techniques that can lead the way to the future design and development of drugs for pregnancy that reduce risk to the health of the fetus and the mother.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
1P01HD039878-01A1
Application #
6593315
Study Section
Special Emphasis Panel (ZHD1)
Project Start
2002-05-02
Project End
2007-03-31
Budget Start
Budget End
Support Year
1
Fiscal Year
2002
Total Cost
Indirect Cost
Name
University of Kansas
Department
Type
DUNS #
016060860
City
Kansas City
State
KS
Country
United States
Zip Code
66160
Dai, Guoli; Bustamante, Juan J; Zou, Yuhong et al. (2011) Maternal hepatic growth response to pregnancy in the mouse. Exp Biol Med (Maywood) 236:1322-32
Mitra, Pallabi; Audus, Kenneth; Williams, Gervan et al. (2011) A comprehensive study demonstrating that p-glycoprotein function is directly affected by changes in pH: implications for intestinal pH and effects on drug absorption. J Pharm Sci 100:4258-68
Alam, S M Khorshed; Konno, Toshihiro; Rumi, M A Karim et al. (2010) Prolactin family of the guinea pig, Cavia porcellus. Endocrinology 151:3918-28
Mitra, Pallabi; Audus, Kenneth L (2010) MRP isoforms and BCRP mediate sulfate conjugate efflux out of BeWo cells. Int J Pharm 384:15-23
Kent, Lindsey N; Konno, Toshihiro; Soares, Michael J (2010) Phosphatidylinositol 3 kinase modulation of trophoblast cell differentiation. BMC Dev Biol 10:97
Mitra, Pallabi; Audus, Kenneth L (2009) Expression and functional activities of selected sulfotransferase isoforms in BeWo cells and primary cytotrophoblast cells. Biochem Pharmacol 78:1475-82
Alam, S M Khorshed; Konno, Toshihiro; Sahgal, Namita et al. (2008) Decidual cells produce a heparin-binding prolactin family cytokine with putative intrauterine regulatory actions. J Biol Chem 283:18957-68
Rytting, Erik; Audus, Kenneth L (2008) Contributions of phosphorylation to regulation of OCTN2 uptake of carnitine are minimal in BeWo cells. Biochem Pharmacol 75:745-51
Yu, Yang; Singh, Umashankar; Shi, Wei et al. (2008) Influence of murine maternal diabetes on placental morphology, gene expression, and function. Arch Physiol Biochem 114:99-110
Bustamante, Juan J; Dai, Guoli; Soares, Michael J (2008) Pregnancy and lactation modulate maternal splenic growth and development of the erythroid lineage in the rat and mouse. Reprod Fertil Dev 20:303-10

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