In vitro and in silico studies of interactions between pesticides and human membrane transporters of xenobiotics ; Etudes in vitro et in silico des interactions entre les pesticides et les transporteurs membranaires humains de xénobiotiques

Pesticides are a very broad category of environmental contaminants with widespread exposure. An increasing number of studies are pointing to suspected links between pesticide exposure and the development of pathologies. Among the key players in the fate and toxicity of xenobiotics are membrane transporters, located in particular at biological barriers. However, the interactions of pesticides with membrane transporters are still poorly characterized in view of the diversity of pesticides. Therefore, the objective of this thesis was to contribute to the improvement of the state of knowledge of interactions between pesticides and human membrane transporters. To do so, a first part of the thesis consisted in studying the interactions between pesticides in a broad sense and a major transporter in toxicology, the P-gp, by means of complementary approaches. The interactions between pesticides and P-gp were studied in silico before being studied in vitro on different cell models, a subline of MCF7 cells selected by resistance to doxorubicin, and the intestinal cell line Caco-2. Then, in a second step, the thesis focused on the interactions of carbamate pesticides with the main human membrane transporters recommended for the study of xenobiotics. Several interactions were thus highlighted at the end of this project. One pesticide was shown to be a P-gp substrate, five were shown to be P-gp inhibitors and two carbamates modulated the activity of the BCRP, OAT3, OCT1, OCT2 and MATE2-K transporters. The results of this thesis provide elements of characterization of the interactions between pesticides and human membrane transporters, which are integrated in the understanding of the toxicokinetic mechanisms that may contribute to the toxicity of these compounds. ; Les pesticides forment une très vaste catégorie de contaminants environnementaux dont l’exposition est généralisée. De plus en plus d’études mettent en exergue des présomptions de liens entre des expositions aux pesticides et la survenue de pathologies. Parmi les ...