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Xénobiotiques hépatotoxiques : études de métabolisme et mécanismes d’action

Abstract : Xenobiotic-induced hepatotoxicity is an extremely rich subject, given the multiple mechanisms and actors involved. This translational work aims to improve ethanol and amanitins (powerful fungal toxins) hepatotoxic mechanisms understanding, in order to provide new elements to optimize the therapeutic management of intoxicated patients. In a first step, we provide additional elements of understanding on macrophages response mechanisms to ethanol. These xenobiotic-cell interactions, shown through the P2X7 receptor induction example, seem to contribute in alcoholic liver damage severity, and testify to the macrophages plasticity in pathological situations. These results suggest in particular the interest of P2X7 receptor antagonist’s development in the treatment of alcoholism. In a second step, we are applied molecular networking, which allows the visualization of complex data acquired by LC-MS/MS, to xenobiotic metabolism study. The acebutolol metabolism example, in the context of voluntary drug intoxication on the one hand, and the in vitro quetiapine metabolism study on the other hand, have provided consistent evidence concerning molecular network interest in this context. In a third and final step, the molecular network application allowed us to rule out the hypothesis of an in vivo and in vitro amanitins metabolism. Moreover, our results show that the hepatocyte-like cellular model of differentiated HepaRG is a relevant model in amanitins study, and show the mitochondrial ROS production implication in these substances toxicity.
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https://tel.archives-ouvertes.fr/tel-03267705
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Submitted on : Tuesday, June 22, 2021 - 3:58:44 PM
Last modification on : Friday, December 10, 2021 - 4:20:09 PM
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  • HAL Id : tel-03267705, version 1

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Brendan Le Daré. Xénobiotiques hépatotoxiques : études de métabolisme et mécanismes d’action. Médecine humaine et pathologie. Université Rennes 1, 2021. Français. ⟨NNT : 2021REN1B005⟩. ⟨tel-03267705⟩

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