Redox-Dependent HMGB1 Isoforms as Pivotal Co-Ordinators of Drug-Induced Liver Injury: Mechanistic Biomarkers and Therapeutic Targets

Abstract

A point-of-care test for HMGB1 and the development of redox and acetyl isoform-targeting antibodies will advance clinical utility. Work is ongoing to validate baseline levels of circulating HMGB1 in healthy volunteers.

Novel circulating- and imaging-based biomarkers to enhance the mechanistic understanding of human drug-induced liver injury

“…HMGB1 is highly conserved between mammalian species and its structure and behaviour between the intracellular (both nuclear and cytosolic) and extracellular compartment has been defined very well elsewhere [39]. The localization and function of HMGB1 are known to be determined by post-translational modifications [40].…”

“…Once the inflammatory cells are activated they can liberate ROS. In oxidizing conditions, fully reduced HMGB1 can be oxidized to disulphide HMGB1 which will act as a turnover, as disulphide HMGB1 has higher affinity for TLR and RAGE, increasing cytokine release and inducing more inflammatory cell recruitment [39]. The disulfide and reduced cysteine form of HMGB1 are mutually exclusive, therefore the redox status of HMGB1 determines the shift between chemoattractant and inflammation, thus driving the function of HMGB1.…”

“…Inflammatory cells (monocytes and macrophages), can undergo HMGB1-acetylation after activation by inflammatory stimuli, leading to protein translocation to the cytoplasm and subsequent excretion to the extracellular compartment [58]. The two different isoforms of HMGB1 mentioned throughout this review are displayed in different temporal profiles allowing differentiation and classification of cell injury and inflammatory event as acetylated HMGB1 is not released from nonimmune cells [39].…”

“…To further investigate the role of HMGB1 in the coordination of the inflammatory response, there has recently been a focus in pre-clinical models on therapeutic interventions to inhibit HMGB1 release and function by using different strategies including exogenous agents (anti-HMGB1 antibody), small molecules inhibitors of HMGB1 and endogenous peptides [39,43]. Neutralizing circulating HMGB1 has been demonstrated to prevent inflammatory cell recruitment and to increase survival after APAP challenge [43].…”

“…To date, in clinical scenarios, the panel of biomarkers utilized to diagnose DILI is based on Hy's law alongside serum albumin and prothrombin time (markers of liver function) to provide a fuller picture of the status of the liver [39,78]. Even though the biomarkers mentioned above have been recognized as fundamental to efforts in translational hepatotoxicity research, many of the reported candidate biomarkers for hepatic drug safety have focused on hepatocyte injury rather than liver function, are still indicators of late stage liver injury, are not always specific to impaired liver and can be affected by other factors -therefore not suitable for early diagnosis and appropriate for treatment implementation.…”