Oxidative Stress in Drug-Induced Liver Injury (DILI): From Mechanisms to Biomarkers for Use in Clinical Practice

Abstract

Idiosyncratic drug-induced liver injury (DILI) is a type of hepatic injury caused by an uncommon drug adverse reaction that can develop to conditions spanning from asymptomatic liver laboratory abnormalities to acute liver failure (ALF) and death. The cellular and molecular mechanisms involved in DILI are poorly understood. Hepatocyte damage can be caused by the metabolic activation of chemically active intermediate metabolites that covalently bind to macromolecules (e.g., proteins, DNA), forming protein adducts—neoantigens—that lead to the generation of oxidative stress, mitochondrial dysfunction, and endoplasmic reticulum (ER) stress, which can eventually lead to cell death. In parallel, damage-associated molecular patterns (DAMPs) stimulate the immune response, whereby inflammasomes play a pivotal role, and neoantigen presentation on specific human leukocyte antigen (HLA) molecules trigger the adaptive immune response. A wide array of antioxidant mechanisms exists to counterbalance the effect of oxidants, including glutathione (GSH), superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPX), which are pivotal in detoxification. These get compromised during DILI, triggering an imbalance between oxidants and antioxidants defense systems, generating oxidative stress. As a result of exacerbated oxidative stress, several danger signals, including mitochondrial damage, cell death, and inflammatory markers, and microRNAs (miRNAs) related to extracellular vesicles (EVs) have already been reported as mechanistic biomarkers. Here, the status quo and the future directions in DILI are thoroughly discussed, with a special focus on the role of oxidative stress and the development of new biomarkers.

Drug‐Induced Liver Injury: Clinical Evidence of N‐Acetyl Cysteine Protective Effects

“…Oxidative stress is well-recognized as a predominant pathogenic process for the development of acute liver failure. As a result, there is already increased evidence describing the implications of oxidative stress in the pathophysiology of diverse liver conditions [ 65 , 66 ], which poses a higher risk of developing acute liver failure upon exposure to hepatotoxic drugs [ 67 ]. Different drug compounds are thought to have different modes in DILI pathogenesis, including prompting mitochondrial dysfunction, as part of the characteristic feature of oxidative stress driven toxicity [ 34 , 68 ].…”

“…Under disease conditions, the immoderate production of radical molecules such as reactive oxygen species (ROS) usually cause direct damage to the biomolecules and eventually impair biochemical processes and cause cellular injury [ 69 ]. Although the liver is well-equipped with substantial antioxidant defences such as GSH, glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase to scavenge ROS, the metabolism of certain drugs can deplete the defence antioxidants and induce a state of oxidative stress that precede adverse liver injuries [ 66 ]. As a prime example, acetaminophen, which is a widely used pharmaceutical drug to moderate pain, is well-studied in the context of DILI, as it remains the leading cause of drug-induced liver failure in many countries, when used above the recommended dose ( Figure 1 ) [ 70 ].…”

Efficacy and Safety of Herbal Medicines in Asia

“…Any action taken involves various environmental and genetic factors, and the degree of liver damage varies. 47…”

“…Once damaged, both innate and adaptive responses emerge and play an essential role in triggering inflammation and tissue injury. 47…”

Zafirlukast ameliorates Docetaxel-induced activation of NOD-like receptor protein 3 (NLRP3) inflammasome, mediated by sirtuin1 (SIRT1) in hepatocytes

“…Ultimately, necrosis and apoptosis of hepatocytes are induced. Direct damage or oxidative stress induced by drugs or their metabolites are the main mechanisms of mitochondrial damage in the progression of DILI [ 7 ]. Firstly, the mitochondrial respiratory chain is inhibited by drugs or their metabolites to block the synthesis of ATP and decrease the energy supply.…”