Redox-Dependent HMGB1 Isoforms as Pivotal Co-Ordinators of Drug-Induced Liver Injury: Mechanistic Biomarkers and Therapeutic Targets.
CONCLUSIONS
High-mobility group box 1 (HMGB1) is a critical protein in the coordination of the inflammatory response in drug-induced liver injury (DILI). HMGB1 is released from necrotic hepatocytes and activated immune cells. The extracellular function of HMGB1 is dependent upon redox modification of cysteine residues that control chemoattractant and cytokine-inducing properties. Existing biomarkers of DILI such as alanine aminotransferase (ALT) have limitations such as lack of sensitivity and tissue specificity that can adversely affect clinical intervention.


BACKGROUND
HMGB1 isoforms have been shown to be more sensitive biomarkers than ALT for predicting DILI development and the requirement for liver transplant following acetaminophen (APAP) overdose. Hepatocyte-specific conditional knockout of HMGB1 has demonstrated the pivotal role of HMGB1 in DILI and liver disease. Tandem mass spectrometry (MS/MS) enables the characterization and quantification of different mechanism-dependent post-translationally modified isoforms of HMGB1.


RESULTS
HMGB1 shows great promise as a biomarker of DILI. However, current diagnostic assays are either too time-consuming to be clinically applicable (MS/MS) or are unable to distinguish between different redox and acetyl isoforms of HMGB1 (ELISA). Additionally, HMGB1 is not liver specific, so while it outperforms ALT (also not liver specific) as a biomarker for the prediction of DILI development, it should be used in a biomarker panel along with liver-specific markers such as miR-122.


CONCLUSIONS
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.
Department of Molecular and Clinical Pharmacology, MRC Centre for Drug Safety Science, University of Liverpool , Liverpool, United Kingdom .
Jonathan D
JD
Lea
Department of Molecular and Clinical Pharmacology, MRC Centre for Drug Safety Science, University of Liverpool , Liverpool, United Kingdom .
Joanna I
JI
Clarke
Department of Molecular and Clinical Pharmacology, MRC Centre for Drug Safety Science, University of Liverpool , Liverpool, United Kingdom .
Niamh
N
McGuire
Department of Molecular and Clinical Pharmacology, MRC Centre for Drug Safety Science, University of Liverpool , Liverpool, United Kingdom .
Daniel J
DJ
Antoine
D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000175:diagnosis* / Q000378:metabolism*; D024243:HMGB1 Protein / Q000032:analysis / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D035683:MicroRNAs / Q000032:analysis / Q000378:metabolism; D010084:Oxidation-Reduction; D000067716:Point-of-Care Testing; D020033:Protein Isoforms / Q000378:metabolism
D015415:Biomarkers; D024243:HMGB1 Protein; C585491:HMGB1 protein, human; C531907:MIRN122 microRNA, human; D035683:MicroRNAs; D020033:Protein Isoforms