OXIDATIVE STRESS IS INVOLVED IN THE IMPAIRMENT OF MRP2 ACTIVITY INDUCED BY IL-1ß IN RAT.

SCHUCK, VIRGINIA S; ANDERMATTEN, ROMINA B; CIRIACI, NADIA; MEDEOT, ANABELA C; SALAS GIMENA; RAZORI, M VALERIA; BAROSSO, ISMAEL R; SANCHEZ POZZI, ENRIQUE J.

Congreso; REUNIÓN DE SOCIEDADES DE BIOCIENCIAS 2021; 2021

Sociedad Argentina de Investigaciones Clínicas

The inflammatory cytokine IL-1ß is increased in inflammatory diseases that are associated with cholestasis. IL-1ß activates signaling pathways that lead to endocytosis of canalicular transporters such as Mrp2. IL-1ß generates reactive oxygen species (ROS) and these species are known to act as signal promoting canalicular transporters endocytosis. Aim: To evaluate the possible role of ROS as signaling mediators in Mrp2 internalization in the cholestasis by IL-1ß using the isolated rat hepatocyte couplet (IRHC) model.Methodology: To prevent the formation of ROS, IRHCs were pre-incubated with the antioxidants vitamin C (1 mM), mannitol (60 mM) for 15 min, followed by addition of cholestatic agent IL-1ß (10 ng/ml) for 20min. Then, they were exposed to chloromethylfluorescein diacetate (2.5 µM, 15 min), converted intracellularly into glutathione methylfluorescein (GMF), Mrp2 substrate. Finally, Mrp2 activity was estimated by the percentage of IRHCs that accumulated GMF in the canalicular vesicle (cVA).Results: (% of control ± SE): IL-1ß significantly reduced Mrp2 activity (cVA: IL-1ß=65±5%a). This was prevented by vitamin C (IL-1ß+VitC=101±5%b) and mannitol (IL- 1ß +M=100±10b). a different from control, b different from IL. P