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.
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