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.

Detailed Molecular Mechanisms Involved in Drug-Induced Non-Alcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis: An Update

“…However, many other antihypertensive agents have been reported to cause liver injuries, even though the precise mechanism involved in the onset of hepatic damage is not clear. Enalapril (ELP) is an angiotensin-converting enzyme (ACE) inhibitor, which is commonly employed for the treatment of cardiovascular diseases, including hypertension and heart failure [ 65 ]. It has been reported that mice treated with ELP alone did not develop liver injury.…”

“…It has been reported that mice treated with ELP alone did not develop liver injury. Differently, the combined treatment of ELP with the synthetic glucocorticoid dexamethasone (DEX) and the glutathione synthesis inhibitor L-buthionine-(S,R)-sulfoximine (BSO) resulted in liver steatosis with increased levels of plasma alanine aminotransferase (ALT), accompanied by myeloperoxidase-positive cells infiltrating hepatic tissue and increased oxidative stress-related factors, such as hepatic heme oxygenase-1, serum hydrogen peroxide and hepatic malondialdehyde [ 65 ]. Moreover, in a clinical case report, ELP was suspected to induce macro- and microvesicular steatosis in association with neutrophil infiltration and Mallory body formation with satellitosis; the patient had a 10-year history of systemic lupus erythematosus, was under corticosteroid therapy for one year (40 mg/day) and taking ELP (10 mg/day) for 2.5 years to treat hypertension.…”

Acute kidney injury model established by systemic glutathione depletion in mice

“…We previously reported several evaluation systems on druginduced liver/kidney injury by using BSO-treated rodents (Iida et al, 2015;Iwamura et al, 2016;Shirai, Oda, Makino, Tsuneyama, & Yokoi, 2017). In our recent studies, was established in BSO-treated normal mice by co-administration of ciprofloxacin (a new quinolone antibacterial drug) and atorvastatin (a blood cholesterol lowering drug) (Matsubara, Oda, Akai, & Yokoi, 2018).…”