Toxicological role of an acyl glucuronide metabolite in diclofenac-induced acute liver injury in mice.
J Appl Toxicol
; 37(5): 545-553, 2017 05.
Article
em En
| MEDLINE
| ID: mdl-27671914
ABSTRACT
The acyl glucuronide (AG) metabolites of carboxylic acid-containing drugs are potentially chemically reactive and are suggested to be implicated in toxicity, including hepatotoxicity, nephrotoxicity and drug hypersensitivity reactions. However, it remains unknown whether AG formation is related to toxicity in vivo. In this study, we sought to determine whether AG is involved in the pathogenesis of liver injury using a mouse model of diclofenac (DIC)-induced liver injury. Mice that were administered DIC alone exhibited significantly increased plasma alanine aminotransferase levels, whereas mice that were pretreated with the UDP-glucuronosyltransferase inhibitor (-)-borneol (BOR) exhibited suppressed alanine aminotransferase levels at 3 and 6 h after DIC administration although not significant at 12 h. The plasma DIC-AG concentrations were significantly lower in BOR- and DIC-treated mice than in mice treated with DIC alone. The mRNA expression levels of chemokine (C-X-C motif) ligand 1 (CXCL1), CXCL2 and the neutrophil marker CD11b were reduced in the livers of mice that had been pretreated with BOR compared to those that had been administered DIC alone, whereas mRNA expression of the macrophage marker F4/80 was not altered. An immunohistochemical analysis at 12 h samples revealed that the numbers of myeloperoxidase- and lymphocyte antigen 6 complex-positive cells that infiltrated the liver were significantly reduced in BOR- and DIC-treated mice compared to mice that were treated with DIC alone. These results indicate that DIC-AG is partly involved in the pathogenesis of DIC-induced acute liver injury in mice by activating innate immunity and neutrophils. Copyright © 2016 John Wiley & Sons, Ltd.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Anti-Inflamatórios não Esteroides
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Diclofenaco
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Glucuronídeos
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Doença Hepática Induzida por Substâncias e Drogas
Limite:
Animals
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article