Differential hepatoprotective role of the cannabinoid CB1 and CB2 receptors in acetaminophen‐induced liver injury
Br J Pharmacol. 2020-04-15; 177(14): 3309-3326
DOI: 10.1111/bph.15051
Read on PubMed
Rivera P(1)(2), Vargas A(2), Pastor A(3), Boronat A(3), López-Gambero AJ(2),
Sánchez-Marín L(2), Medina-Vera D(2), Serrano A(2), Pavón FJ(2)(4), de la Torre
R(3), Agirregoitia E(5), Lucena MI(6), Rodríguez de Fonseca F(2), Decara J(2),
Suárez J(2).
Author information:
(1)Department of Endocrinology, Fundación Investigación Biomédica del Hospital
Infantil Universitario Niño Jesús, Instituto de Investigación Biomédica la
Princesa, Madrid, Spain.
(2)UGC Salud Mental, Hospital Regional Universitario de Málaga, Instituto de
Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga, Málaga, Spain.
(3)Farmacología Integrada y Neurociencia de Sistemas, Institut Hospital del Mar
d’Investigacions Mèdiques (IMIM), Barcelona, Spain.
(4)UGC Corazón, Hospital Universitario Virgen de la Victoria, IBIMA, Universidad
de Málaga, Málaga, Spain.
(5)Department of Physiology, Faculty of Medicine and Nursing, UPV/EHU, Leioa,
Spain.
(6)Servicio de Farmacología Clínica, Hospital Universitario Virgen de la
Victoria, IBIMA, Universidad de Málaga, Málaga, Spain.
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.
© 2020 The British Pharmacological Society.
DOI: 10.1111/bph.15051
PMCID: PMC7312315
PMID: 32167157 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflicts of interest.