The Effect of Pre-eclampsia and HIV on the Expression and Regulation of Drug Transporters in Placenta
Year: 2021
Type: dissertation
Abstract: Disease-mediated changes in the expression and activity of placental ABC and SLC drug transporters have been extensively studied in animal models resulting in altered transplacental passage of their substrates. While these transporters are likely also dysregulated in human placental tissues, translational studies are lacking and thus little is known about expression and regulation of these clinically important drug transporters in patients with Pre-eclampsia (PE) and Human Immunodeficiency Virus (HIV). Moreover, statistics indicate that prescription drug use in pregnancy is on the rise and is likely higher in these two conditions. In two separate studies, we used placental tissues obtained at birth from women with PE and HIV, to investigate the effect of these two diseases on the expression of highly expressed and clinically relevant drug transporters. We further used in vitro cultured placental cells and cultured placental villous explants to further understand the effects of angiogenic factors in the context of PE and ARVs in the context of HIV on the expression of several drug transporters. Our studies demonstrated that both PE and HIV resulted in widespread dysregulation of several placental uptake and efflux transporters from women with clinically diagnosed disease. Additionally, within our PE group, placental angiogenic factor sFlt-1 was significantly induced while VEGF and PLGF were significantly downregulated in PE placentas compared to non-PE controls. These were further investigated in vitro where they were found to play a role in the regulation of BCRP and OATP2B1 expression. Within our HIV group, many women were on prescribed antiretroviral regimens, some of which were found to significantly induce PGP and downregulate OAT4 expression in vitro in human placental explants. Our findings suggest that the protective function of the placenta is compromised in women with PE and HIV with significantly altered expression of clinically important transporters. These translational studies provide key insight and real-world evidence of disease-mediated changes in placental transporter expression. As this may impact fetal health and increase in utero exposure to prescription medications, further studies and closer clinical investigation are needed to determine the impact of disease-induced changes on placental drug transporters and the possible impact on maternal drug-disposition and fetal drug exposure.
Source: TSpace (University of Toronto)
Author: Dea Kojovic
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Award: G2000459427
OpenAlex ID: W3186524160