Role of ERK1/2 in TNFα-induced internalization of Abcc2 in rat hepatocyte couplets.

Autor: Ciriaci N; Instituto de Fisiología Experimental (IFISE) - Facultad de Ciencias Bioquímicas y Farmacéuticas (CONICET - U.N.R.), Suipacha 570, S2002LRL Rosario, Argentina., Andermatten RB; Instituto de Fisiología Experimental (IFISE) - Facultad de Ciencias Bioquímicas y Farmacéuticas (CONICET - U.N.R.), Suipacha 570, S2002LRL Rosario, Argentina., Razori MV; Instituto de Fisiología Experimental (IFISE) - Facultad de Ciencias Bioquímicas y Farmacéuticas (CONICET - U.N.R.), Suipacha 570, S2002LRL Rosario, Argentina., Schuck VS; Instituto de Fisiología Experimental (IFISE) - Facultad de Ciencias Bioquímicas y Farmacéuticas (CONICET - U.N.R.), Suipacha 570, S2002LRL Rosario, Argentina., Miszczuk GS; Instituto de Fisiología Experimental (IFISE) - Facultad de Ciencias Bioquímicas y Farmacéuticas (CONICET - U.N.R.), Suipacha 570, S2002LRL Rosario, Argentina., Medeot AC; Instituto de Fisiología Experimental (IFISE) - Facultad de Ciencias Bioquímicas y Farmacéuticas (CONICET - U.N.R.), Suipacha 570, S2002LRL Rosario, Argentina., Crocenzi FA; Instituto de Fisiología Experimental (IFISE) - Facultad de Ciencias Bioquímicas y Farmacéuticas (CONICET - U.N.R.), Suipacha 570, S2002LRL Rosario, Argentina., Roma MG; Instituto de Fisiología Experimental (IFISE) - Facultad de Ciencias Bioquímicas y Farmacéuticas (CONICET - U.N.R.), Suipacha 570, S2002LRL Rosario, Argentina., Barosso IR; Instituto de Fisiología Experimental (IFISE) - Facultad de Ciencias Bioquímicas y Farmacéuticas (CONICET - U.N.R.), Suipacha 570, S2002LRL Rosario, Argentina., Ruiz ML; Instituto de Fisiología Experimental (IFISE) - Facultad de Ciencias Bioquímicas y Farmacéuticas (CONICET - U.N.R.), Suipacha 570, S2002LRL Rosario, Argentina., Sánchez Pozzi EJ; Instituto de Fisiología Experimental (IFISE) - Facultad de Ciencias Bioquímicas y Farmacéuticas (CONICET - U.N.R.), Suipacha 570, S2002LRL Rosario, Argentina. Electronic address: esanchez@unr.edu.ar.
Jazyk: angličtina
Zdroj: Biochemical pharmacology [Biochem Pharmacol] 2019 Jun; Vol. 164, pp. 311-320. Date of Electronic Publication: 2019 Apr 23.
DOI: 10.1016/j.bcp.2019.04.024
Abstrakt: TNFα is a cytokine whose levels are increased in inflammatory pathologies that are associated with cholestasis. Endocytic internalization of Abcc2 (multidrug resistance-associated protein 2), a canalicular transporter of organic anions that is implicated in the clearance of clinically important drugs, is a phenomenon that occurs in inflammatory liver diseases, and it has been established that cytokines act as mediators. However, the intracellular mechanism involved in this effect remains unknown. The aim of the present work was to characterize the internalization of Abcc2 induced by TNFα and to study the role of ERK1/2 and reactive oxygen species as signaling mediators of transporter internalization. Using rat hepatocyte couplets, we found that TNFα (6.25 pg/ml) induced a decrease in Abcc2 activity estimated by the accumulation of the Abcc2 substrate glutathione methylfluorescein in the canalicular vacuole that was accompanied by internalization of Abcc2 from the canalicular membrane. Inhibition of MEK1/2 (upstream of ERK1/2) partially prevented TNFα effects on Abcc2 internalization and activity impairment. Reactive oxygen species (ROS) scavengers such as vitamin C and mannitol partially prevented both TNFα-induced decrease in Abcc2 activity and ERK1/2 phosphorylation. Apocynin, a NADPH oxidase inhibitor, prevented the increase in ROS and the phosphorylation of ERK1/2 produced by TNFα. Taken together, these results indicate that TNFα activates a pathway involving NADPH oxidase, ROS and MEK1/2-ERK1/2 that is partially responsible for the internalization of Abcc2. This internalization leads to an altered transport activity of Abcc2 that could impair drug disposal, enhancing drug toxicity in patients suffering from inflammatory liver diseases.
(Copyright © 2019. Published by Elsevier Inc.)
Databáze: MEDLINE
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