Establishment of a mouse model for amiodarone‐induced liver injury and analyses of its hepatotoxic mechanism

Abstract

Drug-induced liver injury (DILI) is the most frequent cause of post-marketing warnings and withdrawals. Amiodarone (AMD), an antiarrhythmic, presents a risk of liver injury in humans, and its metabolites, formed by cytochrome P450 3A4, are likely more toxic to hepatocytes than AMD is. However, it remains to be clarified whether the metabolic activation of AMD is involved in liver injury in vivo. In this study, to elucidate the underlying mechanisms of AMD-induced liver injury, mice were administered AMD [1000 mg kg(-1), per os (p.o.)] after pretreatment with dexamethasone [DEX, 60 mg kg(-1), intraperitoneal (i.p.)], which induces P450 expression, once daily for 3 days. The plasma alanine aminotransferase (ALT) levels were significantly increased by AMD administration in the DEX-pretreated mice, and the liver concentrations of desethylamiodarone (DEA), a major metabolite of AMD, were correlated with the changes in the plasma ALT levels. Cytochrome c release into the hepatic cytosol and triglyceride levels in the plasma were increased in DEX plus AMD-administered mice. Furthermore, the ratio of reduced glutathione to oxidized glutathione disulfide in the liver significantly decreased in the DEX plus AMD-administered mice. The increase of ALT levels was suppressed by treatment with gadolinium chloride (GdCl3 ), which is an inhibitor of Kupffer cell function. From these results, it is suggested that AMD and/or DEA contribute to the pathogenesis of AMD-induced liver injury by producing mitochondrial and oxidative stress and Kupffer cell activation. This study proposes the mechanisms of AMD-induced liver injury using an in vivo mouse model.

Assessment of amiodarone-induced phospholipidosis in chimeric mice with a humanized liver

“…The half-life of amiodarone in humans is longer than that in rats, according to the reports by Baronas et al (2007) and Rodrigues et al (2013). These fi ndings may refl ect differences in amiodarone exposure between Takai et al (2016) and the present study, although it is necessary to consider the difference in the dose regimen and animal.…”

“…Hepatic concentrations of amiodarone and desethylamiodarone were higher than those after the administration of 1,000 mg/kg in rats reported by Takai et al (2016). The half-life of amiodarone in humans is longer than that in rats, according to the reports by Baronas et al (2007) and Rodrigues et al (2013).…”

“…2), although Mesens et al (2012) and Takai et al (2016) demonstrated that ALT levels increase after consecutive oral administration of 150 mg/kg amiodarone for 9 days in rats and 1,000 mg/kg in mice, respectively.…”

Identification of Epoxide-Derived Metabolite(s) of Benzbromarone

“…8). Several drugs reportedly eliciting idiosyncratic hepatotoxicities have been documented to be bioactivated mainly by CYP3A4, such as nefazodone (Kalgutkar et al, 2005), zafirlukast (Kassahun et al, 2005), rimonabant (Foster et al, 2013), and amiodarone (Takai et al, 2016;Xuan et al, 2015). CYP3A4 is the major human hepatic P450 enzyme, and the abundance of the enzyme seems unlikely to explain the rare incidence of idiosyncratic events in humans.…”

Mitochondrial dysfunction as a mechanism of drug-induced hepatotoxicity: current understanding and future perspectives

“…This toxicity was found to correlate with levels of the AMD metabolite desethylamiodarone, with increase in plasma triglycerides as well as a decrease in the ratio of reduced/oxidized glutathione in the liver. These changes were suppressed by inhibition of Kupffer cell function, suggesting a role for Kupffer cell activation in AMD-induced liver injury [186]. In a rat model of hepatotoxicity, AMD was shown to increase liver mitochondrial hydrogen peroxide formation and induce cardiolipin peroxidation, accompanied by inhibition of mitochondrial complex I activity and uncoupling of oxidative phosphorylation with decrease in liver ATP levels.…”