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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 CB1 and CB2 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 CB1 (ACEA) and CB2 (JWH015) agonists (10 mg·kg-1 ), or lacking CB1 and CB2 receptors. KEY RESULTS 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. CONCLUSION AND IMPLICATIONS 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.

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.