Guanabenz Attenuates Acetaminophen-Induced Liver Toxicity and Synergizes Analgesia in Mice.
Chem Res Toxicol
; 33(1): 162-171, 2020 01 21.
Article
em En
| MEDLINE
| ID: mdl-31524377
ABSTRACT
Endoplasmic reticulum (ER) stress has been shown to be involved in the hepatotoxicity of acetaminophen (APAP). Guanabenz (GA), a widely known antihypertensive drug, is reported to exhibit an anti-ER stress effect. In this study, we investigated the potential of GA as an antidote against APAP-induced hepatotoxicity. The underlying biochemical mechanisms for the hepatoprotective effect of GA were explored. Here we found that treatment of mice with GA (10 mg/kg) before APAP overdose dramatically prevented APAP-induced liver enzyme elevation and resultant toxicity in mice, as indicated by suppression of elevated serum alanine aminotransferase (ALT) levels and liver histological analysis. Importantly, delayed administration of GA within 6 h after APAP overdose also showed an almost equivalent protective effect against APAP liver toxicity. Mechanistically, several pathways are involved in the protective effect of GA against APAP-induced live toxicity, including attenuation of ER stress and oxidative stress, increased levels of nontoxic phase I and II metabolites of APAP, decrease in the formation of toxic N-acetyl-p-benzoquinone imine (NAPQI), and its subsequent protein binding. Importantly, combination of GA with APAP exhibited synergistic interaction in the latter's analgesic activity, while sparing its antipyretic action. These findings provide the preclinical evidence of GA as a promising antidote for treatment of APAP-induced liver toxicity and raise a possibility of its combination with APAP in clinical settings.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Analgésicos não Narcóticos
/
Substâncias Protetoras
/
Doença Hepática Induzida por Substâncias e Drogas
/
Guanabenzo
/
Acetaminofen
Limite:
Animals
Idioma:
En
Revista:
Chem Res Toxicol
Assunto da revista:
TOXICOLOGIA
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Estados Unidos