Differential hepatoprotective role of the cannabinoid CB 1 and CB 2 receptors in paracetamol-induced liver injury

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 CB and CB receptors in liver fibrogenesis and inflammation. The 2-arachidonoylglycerol (2-AG)-related sign...

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Published in:British journal of pharmacology 2020-07, Vol.177 (14), p.3309-3326
Main Authors: Rivera, Patricia, Vargas, Antonio, Pastor, Antoni, Boronat, Anna, López-Gambero, Antonio Jesús, Sánchez-Marín, Laura, Medina-Vera, Dina, Serrano, Antonia, Pavón, Francisco Javier, de la Torre, Rafael, Agirregoitia, Ekaitz, Lucena, María Isabel, Rodríguez de Fonseca, Fernando, Decara, Juan, Suárez, Juan
Format: Article
Language:English
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Summary: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 CB and CB 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 ·day ) of paracetamol (acetaminophen), previously treated with selective CB (ACEA) and CB (JWH015) agonists (10 mg·kg ), or lacking CB and CB receptors. Acute paracetamol increased the expression of CB , ABHD6 and COX-2, while repeated paracetamol increased that of CB 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 CB and CB increments. Acute paracetamol-exposed CB KO mice had higher expression of the fibrogenic αSMA and the cytokine IL-6 and lower apoptotic cleaved caspase 3. CB 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 CB versus CB receptors on inflammatory/fibrogenic factors related to paracetamol-induced hepatotoxicity should be considered for designing alternative therapies against DILI.
ISSN:0007-1188
1476-5381
DOI:10.1111/bph.15051