Project 3 deals with the proteins known as the Organic Cation Transporter 3 (OCT3), which is present in the placenta at very high levels. OCT3 interacts with a wide variety of drugs (e.g. antidepressants). This study suggests that this particular placental transporter may:
metabolize these drugs and thus protect the fetus from the drugs’ effects, or
transfer these drugs to the fetus and thus expose the fetus to the drugs’ effects
affect the concentrations of these drugs in mother’s blood during pregnancy.
To address these questions, we propose the following specific aims:
Investigate the expression and membrane localization of OCT3 in human placentae at different gestational ages.
Compare the polarized expression of OCT3 in placental syncytiotrophoblast with that in renal tubular cells and intestinal epithelial cells.
Investigate the substrate specificity of the OCT3 using two different functional expression systems (mammalian cell expression and Xenopus laevis oocyte expression), with special emphasis on the overlap between OCT3 and P-glycoprotein in terms of handling of therapeutic drugs.
Study the influence of pregnancy on the expression of OCT in the intestine, kidney and liver in mice and in nonhuman primates. Compare the fetal exposure and/or pharmacokinetics of OCT3-specific therapeutic drugs under pregnant and non-pregnant states between control and OCT3 knockout mice.
Investigate the regulation of OCT3 expression by steroid hormones, with special emphasis on progesterone and potential involvement of the type 1 sigma receptor, using human cell lines.
Investigate the regulation of OCT3 expression by the human immunodeficiency virus transactivator protein Tat using human cell lines stably transfected with HIV-Tat cDNA and also using Tat-expressing transgenic mice. Compare the fetal exposure and/or pharmacokinetics of OCT3-specific therapeutic drugs under pregnant and non-pregnant states between control mice and Tat-expressing transgenic mice.