Rivera_2020_Br.J.Pharmacol__

BACKGROUND AND PURPOSE: Protective mechanisms of the endogenous cannabinoid (eCB) 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-arachidonoyl glycerol (2-AG)-related signaling 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 acetaminophen (APAP), previously treated with selective CB1 (ACEA) and CB2 (JWH015) agonists (10 mg/kg), or lacking CB1 and CB2 receptors. KEY RESULTS: Acute APAP increased the expression of CB2, ABHD6 and COX-2, while repeated APAP increased that of CB1 and COX-2 and decreased that of DAGLbeta. Both acute and repeated APAP decreased the liver content of acylglycerols (2-AG, 2-LG, 2-OG). Human liver samples from a patient suffering APAP hepatotoxicity confirmed CB1 and CB2 increments. Acute APAP-exposed CB2ko mice had higher expression of the fibrogenic alphaSMA and the cytokine IL6, and lower apoptotic cleaved Caspase3. CB1 deficiency enhanced the repeated APAP-induced increases in alphaSMA and cleaved Caspase3, and blocked those of Cyp2e1, TNFalpha, the chemokine MCP1, and the circulating transaminase gammaGT. Although JWH015 reduced the expression of alphaSMA and TNFalpha in acute APAP, ACEA increased the expression of cleaved Caspase3 and MCP1 in repeated APAP. CONCLUSIONS AND IMPLICATIONS: The differential role of CB1 versus CB2 receptors on inflammatory/fibrogenic factors related to APAP-induced hepatotoxicity should be considered for designing alternative therapies against DILI.