ROLE OF P38 MITOGEN ACTIVATED PROTEIN KINASE (MAPK) IN TAUROLITHOCHOLATE (TLC)-INDUCED IMPAIRMENT OF MULTIDRUG RESISTANCE-ASSOCIATED PROTEIN 2 (MRP2) ACTIVITY

ANDERMATTEN, ROMINA B; CIRIACI, NADIA; SCHUCK, VIRGINIA S; RAZORI, M VALERIA; BAROSSO, ISMAEL R.; SÁNCHEZ POZZI, ENRIQUE J

Congreso; REUNIÓN ANUAL DE SOCIEDADES DE BIOCIENCIAS SAIC - SAI - SAFIS; 2020

Sociedad Argentina de Fisiología-Sociedad Argentina de Investigacion Básica

ROLE OF P38 MITOGEN ACTIVATED PROTEIN KINASE (MAPK)IN TAUROLITHOCHOLATE (TLC)-INDUCED IMPAIRMENT OFMULTIDRUG RESISTANCE-ASSOCIATED PROTEIN 2 (MRP2)ACTIVITYAndermatten RB1, Ciriaci N1, Schuck VS1, Razori MV1, Barosso IR1, SánchezPozzi EJ1.1Instituto de Fisiología Experimental, Facultad de Ciencias Bioquímicas yFarmacéuticas, Universidad Nacional de RosarioTLC causes cholestasis inducing internalization of canalicular transporters,Mrp2 among them. In part, this effect is due to a sequential activation ofsphingosine 1-phosphate receptor 2 (S1PR2), adenylyl cyclase, PKA and PI3K,which blocks the spontaneous reinsertion of Mrp2 but does not affect its initialinternalization induced by TLC. Recently, we found that p38 MAPK is alsoimplicated in the actions of TLC on Mrp2 activity independently of S1PR2. Ouraim was to evaluate the role of p38 in Mrp2 internalization using the isolatedperfused rat liver model (IPRL).Methodology: In IPRL, TLC (4.5 μmol/liver) was injected in the portal vein.SB203580, p38 inhibitor (SB, 500 nM), was added to reservoir 10 min beforeTLC. Finally, biliary flow and dinitrophenyl-glutathione (DNPG) excretion weredetermined. Isolated rat hepatocytes were pretreated with S1PR2 [JTE-013(JTE 10 µM)] and PI3K [wortmannin (W 100 nM)] inhibitors and exposed to TLC(2.5 µM). Then, cells were lysed and p38 phosphorylation was analyzed bywestern blot.Results: (% of control ± SEM; n=3). In IPRL, TLC decreased bile flow to aminimum at min 10 post injection (3.5±0.5a) partially recovering at min 30(19.0±3.0a). Similarly, DNPG excretion had a minimum at min 10 (2.1±0.3a) andpartially recovered at min 30 (10.6±1.2a). SB did not prevent the initial decays inbile flow (11.0±2.0a) and DNPG excretion (7.2±2.2a) but significantly improvesrecovery at min 30 (bile flow: 40.6±5.4a,b; DNPG exc.: 25.0±5.9a,b). Activation ofp38 induced by TLC (227±26a) decreased by W (129±7b), whereas, JTE did notaffect it (299±45a).ap