Toxicological role of an acyl glucuronide metabolite in diclofenac-induced acute liver injury in mice.
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.
Department of Drug Safety Sciences, Division of Clinical Pharmacology, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan.
Shingo
S
Oda
Department of Drug Safety Sciences, Division of Clinical Pharmacology, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan.
Yuji
Y
Shirai
Department of Drug Safety Sciences, Division of Clinical Pharmacology, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan.
Sho
S
Akai
Department of Drug Safety Sciences, Division of Clinical Pharmacology, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan.
Akira
A
Nakajima
Department of Molecular and Environmental Pathology, Institute of Health Biosciences, Tokushima University Graduate School, Tokushima, 770-8503, Japan.
Koichi
K
Tsuneyama
Department of Drug Safety Sciences, Division of Clinical Pharmacology, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan.
Tsuyoshi
T
Yokoi
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics* / Q000633:toxicity*; D001711:Biotransformation; D039481:CD11b Antigen / Q000378:metabolism; D001892:Camphanes / Q000494:pharmacology; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism* / Q000473:pathology; D054360:Chemokine CXCL1 / Q000378:metabolism; D054426:Chemokine CXCL2 / Q000378:metabolism; D004008:Diclofenac / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics* / Q000633:toxicity*; D005260:Female; D020719:Glucuronides / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors; D008099:Liver / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009195:Peroxidase / Q000378:metabolism
C487366:1-O-(2-((2',6'-dichlorophenyl)amino)phenylacetyl)glucopyranuronic acid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D039481:CD11b Antigen; D001892:Camphanes; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; C475895:Cxcl1 protein, mouse; C404915:Cxcl2 protein, mouse; D020719:Glucuronides; D004008:Diclofenac; D009195:Peroxidase; D014453:Glucuronosyltransferase; D000410:Alanine Transaminase; C022871:isoborneol
acyl glucuronide; animal model; diclofenac; drug-induced liver injury; neutrophil