Drug-induced toxicity on mitochondria and lipid metabolism: Mechanistic diversity and deleterious consequences for the liver

Abstract

Numerous investigations have shown that mitochondrial dysfunction is a major mechanism of drug-induced liver injury, which involves the parent drug or a reactive metabolite generated through cytochromes P450. Depending of their nature and their severity, the mitochondrial alterations are able to induce mild to fulminant hepatic cytolysis and steatosis (lipid accumulation), which can have different clinical and pathological features. Microvesicular steatosis, a potentially severe liver lesion usually associated with liver failure and profound hypoglycemia, is due to a major inhibition of mitochondrial fatty acid oxidation (FAO). Macrovacuolar steatosis, a relatively benign liver lesion in the short term, can be induced not only by a moderate reduction of mitochondrial FAO but also by an increased hepatic de novo lipid synthesis and a decreased secretion of VLDL-associated triglycerides. Moreover, recent investigations suggest that some drugs could favor lipid deposition in the liver through primary alterations of white adipose tissue (WAT) homeostasis. If the treatment is not interrupted, steatosis can evolve toward steatohepatitis, which is characterized not only by lipid accumulation but also by necroinflammation and fibrosis. Although the mechanisms involved in this aggravation are not fully characterized, it appears that overproduction of reactive oxygen species by the damaged mitochondria could play a salient role. Numerous factors could favor drug-induced mitochondrial and metabolic toxicity, such as the structure of the parent molecule, genetic predispositions (in particular those involving mitochondrial enzymes), alcohol intoxication, hepatitis virus C infection, and obesity. In obese and diabetic patients, some drugs may induce acute liver injury more frequently while others may worsen the pre-existent steatosis (or steatohepatitis).

Role of endoplasmic reticulum stress in drug‐induced toxicity

“…2008; Begriche et al. 2011). Recently, amiodarone was shown to induce ER stress in thyrocytes and lung epithelial cells (Mahavadi et al.…”

“…The most common adverse effects of these compounds include GI manifestations, drowsiness, extrapyramidal symptoms, cardiac effects, elevation of liver enzymes, and obesity, which can be associated with insulin resistance and fatty liver (Melkersson and Dahl 2003; Begriche et al. 2011; De Fazio et al. 2015; Rojo et al.…”

“…In addition, diclofenac is able to induce direct mitochondrial dysfunction (Begriche et al. 2011; Porceddu et al. 2012; Massart et al.…”

Valproic acid induced acute liver injury resulting in hepatic encephalopathy- a case report and literature review

“…Oxidative stress and some genetic factors have been speculated widely as the key mechanisms for hepatotoxicity [7]. Microvesicular hepatosteatosis is a typical feature of VPA toxicity and is suggestive of mitochondrial involvement especially involving the β-oxidation [8]. The recent study by Komulainen et al showed the effects of VPA on mitochondria using the HepG2 cell in vitro model and further suggested an essential role of mitochondria; VPA inhibited mitochondrial respiration resulting in mitochondrial dysfunction, oxidative stress, and increased cell death [9,10].…”

Mitochondria as a pharmacological target: Magnum overview

“…There is mounting evidence of the mitotoxicity of certain antidiabetic (e.g., metformin) (11), anticancer (e.g., doxorubicin) (13), antiparasitic (e.g., atovaquone) (14), antiviral (e.g., zidovudine) (15), antiepileptic (valproic acid [VPA]) (10), anesthetic (e.g., propofol) (16), anti-inflammatory (e.g., indomethacin) (17), and antiarrhythmic (e.g., carvedinol) (11) drugs. Therefore, taking such drugs can lead to organ damage, particularly damage to the liver (18), kidneys, heart (19), or skeletal muscles (20). Interestingly, these issues affect the most aerobically poised organs (heart and kidneys) or organs exposed to higher concentrations of the drug (liver).…”