Modulation of NRF2/ARE pathway- and cell death-related genes during drug-induced liver injury

• Published in: Human & experimental toxicology 2021-12, Vol.40 (12), p.2223-2236
• Main Authors: Ghanim, BY, Ahmad, MI, Abdallah, QM, Qatouseh, LA, Qinna, NA
• Format: Article
• Language: English
• Subjects: Acetaminophen; Animals; Antioxidants; Apoptosis; Biocompatibility; Biomarkers; Cell death; Cell Death - genetics; Cell survival; Cells, Cultured; Chemical and Drug Induced Liver Injury - genetics; Chemical and Drug Induced Liver Injury - pathology; Depletion; Drug dosages; Gene expression; Genes; Glutathione - metabolism; Hemorrhage; Hepatocytes; Hepatocytes - drug effects; Hepatocytes - metabolism; Hepatotoxicity; HMGB1 protein; Injuries; Liver; Liver - drug effects; Liver - metabolism; Liver - pathology; Male; Mice; Mice, Inbred C57BL; Modulation; Mortality; Necrosis; NF-E2-Related Factor 2 - genetics; Oxidative stress; Signal Transduction; Superoxide Dismutase - metabolism; Translocation
• ISSN: 0960-3271; 1477-0903
• DOI: 10.1177/09603271211027947

Transcriptional factor NRF2 is an emerging tool in reviewing mechanistic behavior of drug-specific injury pathways. Drug-induced liver injury (DILI) represents a major clinical concern that often manifests oxidative stress and cell death. Despite the pivotal role of NRF2 pathway in liver pathologies, it is questioned whether NRF2 activation or regulatory efficiency could be hindered in by the severity of DILI and progression of cell death. In this study, we evaluate NRF2 as a biomarker to DILI in comparison to severity of injury as well as explore stress mediating factors affecting Nrf2 expression. In vivo DILI model was established in C57BL/6 mice by acetaminophen (APAP) at different toxic doses, confirmed by dose-dependent liver pathological changes and accompanied with in vitro time- and dose-dependent depletion of GSH and SOD in isolated primary mouse hepatocytes. Increase in liver NRF2 translocation and cytosolic content was observed in 70 mg/kg APAP-treated mice. At this subtoxic dose, liver Nrf2 transcription was increased in mice by 18.3-fold, a prominent downregulation was seen in ARE (antioxidant response element) genes; Hmox1, Nqo1 and Glcm, and apoptotic Bcl2 regulating genes. In addition, upregulation in necrosis inducer Parp2 was associated to downregulation in Hmgb1. Collectively, expression of genes related to cell survival were regulated at mild APAP hepatotoxicity. By increasing APAP dose, hemorrhagic necrosis and impaired genetic transcription in both Nrf2 and several other genes were evident. In conclusion, NRF2/ARE system and cell death modulation is halted by the increase of chemical stress and found directly associated with DILI severity.