RT Journal Article
T1 Differential hepatoprotective role of the cannabinoid CB1 and CB2 receptors in paracetamol-induced liver injury.
A1 Rivera, Patricia
A1 Vargas, Antonio
A1 Pastor, Antoni
A1 Boronat, Anna
A1 Lopez-Gambero, Antonio Jesus
A1 Sanchez-Marin, Laura
A1 Medina-Vera, Dina
A1 Serrano, Antonia
A1 Pavon, Francisco Javier
A1 de-la-Torre, Rafael
A1 Agirregoitia, Ekaitz
A1 Lucena, Maria Isabel
A1 Rodriguez-de-Fonseca, Fernando
A1 Decara, Juan
A1 Suarez, Juan
K1 Animals
K1 Cannabinoids
K1 Chemical and Drug Induced Liver Injury, Chronic
K1 Disease Models, Animal
AB Protective mechanisms of the endogenous cannabinoid system against drug-induced liver injury (DILI) are actively being investigated regarding the differential regulatory role of the cannabinoid CB1 and CB2 receptors in liver fibrogenesis and inflammation. The 2-arachidonoylglycerol (2-AG)-related signalling receptors and enzymatic machinery, and inflammatory/fibrogenic factors were investigated in the liver of a mouse model of hepatotoxicity induced by acute and repeated overdoses (750 mg·kg-1 ·day-1 ) of paracetamol (acetaminophen), previously treated with selective CB1 (ACEA) and CB2 (JWH015) agonists (10 mg·kg-1 ), or lacking CB1 and CB2 receptors. Acute paracetamol increased the expression of CB2 , ABHD6 and COX-2, while repeated paracetamol increased that of CB1 and COX-2 and decreased that of DAGLβ. Both acute paracetamol and repeated paracetamol decreased the liver content of acylglycerols (2-AG, 2-LG and 2-OG). Human liver samples from a patient suffering APAP hepatotoxicity confirmed CB1 and CB2 increments. Acute paracetamol-exposed CB2 KO mice had higher expression of the fibrogenic αSMA and the cytokine IL-6 and lower apoptotic cleaved caspase 3. CB1 deficiency enhanced the repeated APAP-induced increases in αSMA and cleaved caspase 3 and blocked those of CYP2E1, TNF-α, the chemokine CCL2 and the circulating γ-glutamyltransferase (γGT). Although JWH015 reduced the expression of αSMA and TNF-α in acute paracetamol, ACEA increased the expression of cleaved caspase 3 and CCL2 in repeated paracetamol. The differential role of CB1 versus CB2 receptors on inflammatory/fibrogenic factors related to paracetamol-induced hepatotoxicity should be considered for designing alternative therapies against DILI.
PB John Wiley & Sons
YR 2020
FD 2020-06-24
LK http://hdl.handle.net/10668/15235
UL http://hdl.handle.net/10668/15235
LA en
NO Rivera P, Vargas A, Pastor A, Boronat A, López-Gambero AJ, Sánchez-Marín L, et al. Differential hepatoprotective role of the cannabinoid CB1 and CB2 receptors in paracetamol-induced liver injury. Br J Pharmacol. 2020 Jul;177(14):3309-3326
DS RISalud
RD Apr 10, 2025