Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.734198
Title: Comparative analyses of ABC transporters and metabolising enzymes in human and rat placental models
Author: Taylor, Louise
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2013
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Abstract:
The placenta provides a protective barrier for the developing foetus during gestation. Physiological barriers including the placenta, liver, kidney, intestine and blood-brain barrier are known to express ATP-Binding cassette transporters (ABC transporters) and metabolising enzymes. These specialised proteins have the ability to transport or metabolise xenobiotics. There is evidence to suggest that ABC transporters and metabolising enzymes are located at the interface between the maternal and foetal blood supplies (a cell layer referred to as the syncytiotrophoblast) and therefore may help protect the foetus from harmful xenobiotics. During new compound development prenatal developmental toxicity testing forms an important part of safety assessment. In order to predict potential toxicity of a new chemical entity to humans, rodent and non-rodent species are currently used. This thesis investigates the rat and human placental barrier properties in order to help facilitate our knowledge of species differences and contribute to our understanding of the limitations of these surrogate models. The approaches taken include: genomic analyses using microarray data to compare the overall expression of ABC transporters and metabolising enzymes throughout gestation in both species, immunohistochemical techniques to localise transporters and metabolising enzymes in the rat placenta, and in vitro functionality assays of selected transporters performed in rat and human placental cell line models. The main findings have shown a similar mRNA expression level of ABCG2/BCRP (breast cancer resistance protein) throughout gestation in the rat and human, however different mRNA expression levels of other transporters (slco4a1/oatp4a1 in particular) and metabolising enzymes were also highlighted. Immunohistochemistry localised selected transporters to the syncytiotrophoblast region of the rat placenta (the interface of maternal and foetal circulations). Functional in vitro assays were successfully utilised in rat and human placental cell lines which showed functional ABCB1/P-gp in both species. Overall, these findings provide a genomic characterisation of the rat and human protective placental barrier properties and show transporter functionality in in vitro cell-based assays which will prove useful in prenatal and developmental toxicity tests. Alternatives to using animals have been explored by using functional in vitro assays which could potentially be implored during the new compound discovery phase. This could help to make animal testing more selective for given compounds and ensures the new chemical entity is being tested in the model closest resembling the human.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.734198  DOI: Not available
Keywords: Rat ; Human ; Transporters ; Placenta
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