title: Establishment of a mouse model of enalapril-induced liver injury and investigation of the pathogenesis.
abstract: Drug-induced liver injury (DILI) is a major concern in drug development and clinical drug therapy. Since the underlying mechanisms of DILI have not been fully understood in most cases, elucidation of the hepatotoxic mechanisms of drugs is expected. Although enalapril (ELP), an angiotensin-converting enzyme inhibitor, has been reported to cause liver injuries with a low incidence in humans, the precise mechanisms by which ELP causes liver injury remains unknown. In this study, we established a mouse model of ELP-induced liver injury and analyzed the mechanisms of its hepatotoxicity. Mice that were administered ELP alone did not develop liver injury, and mice that were pretreated with a synthetic glucocorticoid dexamethasone (DEX) and a glutathione synthesis inhibitor l-buthionine-(S,R)-sulfoximine (BSO) exhibited liver steatosis without significant increase in plasma alanine aminotransferase (ALT). In mice pretreated with DEX and BSO, ALT levels were significantly increased after ELP administration, suggesting that hepatic steatosis sensitized the liver to ELP hepatotoxicity. An immunohistochemical analysis showed that the numbers of myeloperoxidase-positive cells that infiltrated the liver were significantly increased in the mice administered DEX/BSO/ELP. The levels of oxidative stress-related factors, including hepatic heme oxygenase-1, serum hydrogen peroxide and hepatic malondialdehyde, were elevated in the mice administered DEX/BSO/ELP. The involvement of oxidative stress in ELP-induced liver injury was further supported by the observation that tempol, an antioxidant agent, ameliorated ELP-induced liver injury. In conclusion, we successfully established a model of ELP-induced liver injury in DEX-treated steatotic mice and demonstrated that oxidative stress and neutrophil infiltration are involved in the pathogenesis of ELP-induced liver injury.
authors.affiliation: Department of Drug Safety Sciences, Division of Clinical Pharmacology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Shirai
authors.affiliation: Department of Drug Safety Sciences, Division of Clinical Pharmacology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Oda
authors.affiliation: Department of Drug Safety Sciences, Division of Clinical Pharmacology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Sayaka
authors.initials: S
authors.lastname: Makino
authors.affiliation: Department of Pathology and Laboratory Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Tsuneyama
authors.affiliation: Department of Drug Safety Sciences, Division of Clinical Pharmacology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Yokoi
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D056486:Chemical and Drug Induced Liver Injury; D004195:Disease Models, Animal; D004656:Enalapril / Q000009:adverse effects*; D005978:Glutathione / Q000032:analysis / Q000378:metabolism; D019803:Glutathione Disulfide / Q000032:analysis / Q000378:metabolism; D008099:Liver / Q000737:chemistry / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects
chemical_list: D000975:Antioxidants; D004656:Enalapril; D005978:Glutathione; D019803:Glutathione Disulfide