Drug‐induced liver injury through mitochondrial dysfunction: mechanisms and detection during preclinical safety studies

Abstract

Mitochondrial dysfunction is a major mechanism whereby drugs can induce liver injury and other serious side effects such as lactic acidosis and rhabdomyolysis in some patients. By severely altering mitochondrial function in the liver, drugs can induce microvesicular steatosis, a potentially severe lesion that can be associated with profound hypoglycaemia and encephalopathy. They can also trigger hepatic necrosis and/or apoptosis, causing cytolytic hepatitis, which can evolve into liver failure. Milder mitochondrial dysfunction, sometimes combined with an inhibition of triglyceride egress from the liver, can induce macrovacuolar steatosis, a benign lesion in the short term. However, in the long term this lesion can evolve in some individuals towards steatohepatitis, which itself can progress to extensive fibrosis and cirrhosis. As liver injury caused by mitochondrial dysfunction can induce the premature end of clinical trials, or drug withdrawal after marketing, it should be detected during the preclinical safety studies. Several in vitro and in vivo investigations can be performed to determine if newly developed drugs disturb mitochondrial fatty acid oxidation (FAO) and the oxidative phosphorylation (OXPHOS) process, deplete hepatic mitochondrial DNA (mtDNA), or trigger the opening of the mitochondrial permeability transition (MPT) pore. As drugs can be deleterious for hepatic mitochondria in some individuals but not in others, it may also be important to use novel animal models with underlying mitochondrial and/or metabolic abnormalities. This could help us to better predict idiosyncratic liver injury caused by drug-induced mitochondrial dysfunction.

Role of endoplasmic reticulum stress in drug‐induced toxicity

“…Actually, drugs can induce oxidative stress via several mechanisms including by increasing reactive oxygen species (ROS) production by the dysfunctional mitochondria and higher NADPH oxidase activity and by reducing cellular antioxidant defenses (Labbe et al. 2008; Baillie and Rettie 2011; Begriche et al. 2011; Leung et al.…”

“…Importantly, troglitazone caused several cases of fatal liver failure and was thus withdrawn from the market (Labbe et al. 2008). The role and mechanisms of ER stress in sertraline and troglitazone‐induced hepatotoxicity have been discussed in a recent review (Chen et al.…”

“…Since numerous drugs are able to impair mitochondrial function (Labbe et al. 2008; Begriche et al. 2011; Porceddu et al.…”

Toxicidad hepática causada por medicamentos: revisión estucturada

“…La hepatotoxicidad se relaciona con disfunción mitocondrial, por inhibición de la respiración celular o alteración en la oxidación β de los ácidos grasos (26,27), lo que genera apoptosis, necrosis, autofagia y, con ello, muerte celular (28,29). Las principales manifestaciones clínico-patológi-cas de la hepatotoxicidad y sus hallazgos histológicos son: a.…”

“…Hepatitis aguda (caracterizada por inflamación parenquimal, necrosis y células de Kupffer en los sinusoides); b. Hepatitis crónica (fibrosis); c. Hepatitis fulminante (necrosis e inflamación); d. Hepatitis colestásica (inflamación y daño hepático); e. Colestasis (tapones biliares en zona 3); f. Síndrome de desvanecimiento de conductos biliares (daño en conductos biliares, colestasis e inflamación); g. Hepatitis granulomatosa (granulomas en tractos portales o parénquima); h. Esteatosis macrovesicular (gotas de lípidos en el citoplasma del hepatocito); i. Esteatosis microvesicular (diminutas gotas de lípidos en el citoplasma del hepatocito); y j. Esteatohepatitis (esteatosis, inflamación lobular, hepatocitos englobados y fibrosis pericelular) (12,(29)(30)(31).…”