2026-06-06T19:03:47Zhttps://riuma.uma.es/rest/oai/request

oai:riuma.uma.es:10630/402682026-02-03T11:26:58Zcom_10630_2254col_10630_37953

00925njm 22002777a 4500 dc Rivera-González, Patricia author Pastor, Antoni author Arrabal, Sergio author Decara, Juan Manuel author Vargas, Antonio author Sanchez, Laura author Pavón, Francisco javier author Serrano, Antonia author Bautista, Dolores author Boronat, Anna author De la Torre, Rafael author Baixeras-Llano, Elena author Lucena-González, María Isabel author Rodriguez de Fonseca, Fernando author Suárez-Pérez, Juan author 2017-10-06 Protective mechanisms against drug-induced liver injury are actively being searched to identify new therapeutic targets. Among them, the anti-inflammatory N-acyl ethanolamide (NAE)-peroxisome proliferators activated receptor alpha (PPARα) system has gained much interest after the identification of its protective role in steatohepatitis and liver fibrosis. An overdose of paracetamol (APAP), a commonly used analgesic/antipyretic drug, causes hepatotoxicity, and it is being used as a liver model. In the present study, we have analyzed the impact of APAP on the liver NAE-PPARα system. A dose-response (0.5–5–10–20 mM) and time-course (2–6–24 h) study in human HepG2 cells showed a biphasic response, with a decreased PPARα expression after 6-h APAP incubation followed by a generalized increase of NAE-PPARα system-related components (PPARα, NAPE-PLD, and FAAH), including the NAEs oleoyl ethanolamide (OEA) and docosahexaenoyl ethanolamide, after a 24-h exposure to APAP. These results were partially confirmed in a time-course study of mice exposed to an acute dose of APAP (750 mg/kg). The gene expression levels of Pparα and Faah were decreased after 6 h of treatment and, after 24 h, the gene expression levels of Nape-pld and Faah, as well as the liver levels of OEA and palmitoyl ethanolamide, were increased. Repeated APAP administration (750 mg/kg/day) up to 4 days also decreased the expression levels of PPARα and FAAH, and increased the liver levels of NAEs. A resting period of 15 days completely restored these impairments. Liver immunohistochemistry in a well-characterized human case of APAP hepatotoxicity confirmed PPARα and FAAH decrements. Histopathological and hepatic damage (Cyp2e1, Caspase3, αSma, Tnfα, and Mcp1)-related alterations observed after repeated APAP administration were aggravated in the liver of Pparα-deficient mice. Our results demonstrate that the anti-inflammatory NAE-PPARα signaling system is implicated in liver toxicity after exposure to APAP overdose, and may contribute to its recovery through a long-term time-dependent response. Patricia Rivera, Antoni Pastor, Sergio Arrabal, Juan Decara, Antonio Vargas, Laura Sánchez-Marín, Francisco J Pavón, Antonia Serrano, Dolores Bautista, Anna Boronat, Rafael de la Torre, Elena Baixeras, M Isabel Lucena, Fernando R de Fonseca, Juan Suárez. Acetaminophen-Induced Liver Injury Alters the Acyl Ethanolamine-Based Anti-Inflammatory Signaling System in Liver. Front Pharmacol. 2017 Oct 6:8:705. doi: 10.3389/fphar.2017.00705 https://hdl.handle.net/10630/40268 10.3389/fphar.2017.00705 Hepatotoxicidad Hígado - Heridas y lesiones Paracetamol - Toxicidad Acetaminophen-Induced Liver Injury Alters the Acyl Ethanolamine-Based Anti-Inflammatory Signaling System in Liver.