Differential hepatoprotective role of the cannabinoid CB1 and CB2 receptors in paracetamol-induced liver injury

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 center dot kg(-1)center dot day(-1)) of paracetamol (acetaminophen), previously treated with selective CB1 (ACEA) and CB2 (JWH015) agonists (10 mg center dot 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 DAGL beta. 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 alpha SMA and the cytokine IL-6 and lower apoptotic cleaved caspase 3. CB1 deficiency enhanced the repeated APAP-induced increases in alpha SMA and cleaved caspase 3 and blocked those of CYP2E1, TNF-alpha, the chemokine CCL2 and the circulating gamma-glutamyltransferase (gamma GT). Although JWH015 reduced the expression of alpha SMA and TNF-alpha 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.