Protein tyrosine phosphatase 1B deficiency protects against paracetamol-induced hepatotoxicity

Abstract

Resumen del póster presentado al XXXIV Congreso de la Sociedad Española de Bioquímica y Biología Molecular, celebrado en Barcelona del 5 al 8 de septiembre de 2011.Acetaminophen (APAP) is an analgesic and antipyretic drug safe at therapeutic doses but its overdose causes liver injury. Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of growth factor signalling and modulate the balance between survival and cell death. Our purpose was to study if PTP1B plays a role in APAP-induced hepatotoxicity. APAP induced hepatotoxicity was evaluated in immortalized hepatocytes from wild-type (PTP1B+/+) and PTP1B-/- mice. PTP1B deficiency protected against GSH depletion, elevation of ROS, cell cycle arrest and apoptotic/necrotic cell death. At the molecular level, phosphorylation of JNK and p38 was higher in APAPtreated wild-type hepatocytes compared to PTP1B-/- cells. Regarding survival signaling, phosphorylation of IGF-IR, levels of IRS1 and IRS2 and activation of Akt decreased in wild-type hepatocytes but not in PTP1B-/-cells. Therefore, the expression of the anti-apoptotic proteins BclxL and Mcl-1 was reduced in wild-type cells, but it was maintained in PTP1B-/- hepatocytes. We confirmed these results in the liver of wild type and PTP1B-/- mice after ip APAP injection. We found increased JNK phosphorylation at 1-6 h post-injection. Survival signaling including phosphorylation of IGF-IR, levels of IRS1 and activation of Akt was decreased at 6 h after APAP injection in wild-type mice, but not in PTP1B-/- mice. GSH depletion and ROS levels were attenuated in PTP1B-/- livers in parallel with an increase in nuclear Nrf2 accumulation and HO-1 induction. Finally, treatment of human hepatocytes with APAP increased PTP1B expression and activation of JNK and p38, decreasing survival signaling and cellular viability. Our data suggest that PTP1B might be a target against APAPinduced hepatotoxicity.SAF2009-08114 MCINN.Peer Reviewe