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Differential hepatoprotective role of the cannabinoid CB 1 and CB 2 receptors in paracetamol‐induced liver injury
Author(s) -
Rivera Patricia,
Vargas Antonio,
Pastor Antoni,
Boronat Anna,
LópezGambero Antonio Jesús,
SánchezMarín Laura,
MedinaVera Dina,
Serrano Antonia,
Pavón Francisco Javier,
Torre Rafael,
Agirregoitia Ekaitz,
Lucena María Isabel,
Rodríguez de Fonseca Fernando,
Decara Juan,
Suárez Juan
Publication year - 2020
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.15051
Subject(s) - acetaminophen , pharmacology , cannabinoid , liver injury , cannabinoid receptor , receptor , endocannabinoid system , chemistry , medicine , agonist
Background and Purpose 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 1 and CB 2 receptors in liver fibrogenesis and inflammation. Experimental Approach 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 CB 1 (ACEA) and CB 2 (JWH015) agonists (10 mg·kg −1 ), or lacking CB 1 and CB 2 receptors. Key Results Acute paracetamol increased the expression of CB 2 , ABHD6 and COX‐2, while repeated paracetamol increased that of CB 1 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 1 and CB 2 increments. Acute paracetamol‐exposed CB 2 KO mice had higher expression of the fibrogenic αSMA and the cytokine IL‐6 and lower apoptotic cleaved caspase 3. CB 1 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. Conclusion and Implications The differential role of CB 1 versus CB 2 receptors on inflammatory/fibrogenic factors related to paracetamol‐induced hepatotoxicity should be considered for designing alternative therapies against DILI.