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

ABSTRACT:

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.

SUBMITTER: Rivera P 

PROVIDER: S-EPMC7312315 | biostudies-literature |

REPOSITORIES: biostudies-literature