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Interspecies variability between man, rabbit and rat in function and structure of major xenobiotic transport proteins in the placenta
Project
Project code: BfR-CHS-08-1322-417
Contract period: 01.04.2009
- 31.12.2011
Purpose of research: Applied research
According to OECD test guidelines 414 and 416 developmental toxicity studies are normally performed in animals, i.e. in rats or rabbits. In some cases the obtained data cannot be di-rectly transferred to the situation in humans (Newman et al., 1993) as there are major inter-species differences regarding the anatomy of the placenta as well as the expression of pro-teins involved in metabolism and transport of xenobiotics. Further gain of knowledge about interspecies variability in this area (together with better knowledge of substrate specificity of these transporters) would contribute to a better prediction of the placental passage of xenobiotics in rabbits, rats and humans and to a better risk assessment regarding the extrapolation from animal data to the human situation.One of the variables that determine the toxicity of a substance to the unborn child is the extent of transplacental passage. The extent of the transplacental passage of xenobiotics is largely determined by the presence of transport systems in (syncytio-)trophoblasts. Depend-ing on the localisation of transporters and direction of the transport (maternal - foetal oder foetal - maternal) the passage of a substance might either be facilitated or prevented/aggravated.Some proteins of the ABC transporter family are highly expressed in tissues that are either particular susceptible to damage by xenobiotics (e.g. brain, testis) or highly exposed (e.g. liver, kidneys) and seem to play a major role in the toxicokinetics e.g. in the blood-placenta passage.The expression of these ABC transporters in different species is an important criterion for the extrapolation from animal data to humans but only little research is done on this topic, esp. in the rabbit where the sequences of the ABC transporters Mdr1 (multidrug resistance 1) and Bcrp (breast cancer resistance protein) are not even known.
Section overview
Subjects
- Physiology of Nutrition
