Villanueva-Paz, MarinaMorán, LauraLópez-Alcántara, NuriaFreixo, CristianaAndrade, Raúl J.Lucena, M IsabelCubero, Francisco Javier2022-05-232022-05-232021-03-05Villanueva-Paz M, Morán L, López-Alcántara N, Freixo C, Andrade RJ, Lucena MI, et al. Oxidative Stress in Drug-Induced Liver Injury (DILI): From Mechanisms to Biomarkers for Use in Clinical Practice. Antioxidants (Basel). 2021 Mar 5;10(3):390http://hdl.handle.net/10668/3663Idiosyncratic 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.enAtribución 4.0 Internacionalhttp://creativecommons.org/licenses/by/4.0/DILIOxidative stressRisk factorsBiomarkersMechanismsEstrés oxidativoFactores de riesgoBiomarcadoresMedical Subject Headings::Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Molecular Mechanisms of Pharmacological Action::AntioxidantsMedical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Oxidoreductases::Peroxidases::Glutathione PeroxidaseMedical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Oxidoreductases::Peroxidases::CatalaseMedical Subject Headings::Chemicals and Drugs::Macromolecular Substances::Multiprotein Complexes::InflammasomesMedical Subject Headings::Health Care::Health Care Facilities, Manpower, and Services::Health Facilities::LaboratoriesMedical Subject Headings::Phenomena and Processes::Metabolic Phenomena::Metabolism::Oxidative StressMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Peptides::Oligopeptides::GlutathioneMedical Subject Headings::Anatomy::Cells::Epithelial Cells::HepatocytesMedical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Oxidoreductases::Superoxide DismutaseMedical Subject Headings::Chemicals and Drugs::Biological Factors::Biological MarkersMedical Subject Headings::Phenomena and Processes::Immune System Phenomena::Immunity::Adaptive ImmunityMedical Subject Headings::Anatomy::Cells::Cellular Structures::Intracellular Space::Cytoplasm::Cytoplasmic Structures::Organelles::MitochondriaMedical Subject Headings::Chemicals and Drugs::Biological Factors::Antigens::Antigens, Surface::Histocompatibility Antigens::HLA AntigensMedical Subject Headings::Anatomy::Cells::Cellular Structures::Intracellular Space::Cytoplasm::Cytoplasmic Structures::Organelles::Endoplasmic ReticulumMedical Subject Headings::Diseases::Digestive System Diseases::Liver Diseases::Hepatic Insufficiency::Liver Failure::Liver Failure, AcuteMedical Subject Headings::Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell DeathMedical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Hydrolases::Acid Anhydride Hydrolases::GTP Phosphohydrolases::GTP-Binding ProteinsMedical Subject Headings::Chemicals and Drugs::Nucleic Acids, Nucleotides, and Nucleosides::Antisense Elements (Genetics)::RNA, Antisense::MicroRNAsMedical Subject Headings::Chemicals and Drugs::Chemical Actions and Uses::Toxic Actions::Noxae::Oxidantsreview article33807700Acceso abierto10.3390/antiox100303902076-3921PMC8000729