title: Current understanding of the mechanisms of idiosyncratic drug-induced agranulocytosis.
abstract: BACKGROUND
  Idiosyncratic drug-induced agranulocytosis (IDIAG) is a life-threatening adverse reaction characterized by an absolute neutrophil count < 500 cells/μl of blood. It shares many of the characteristics of other idiosyncratic drug reactions (IDRs), and this presumably reflects mechanistic similarities.
  
  
  METHODS
  This review describes the evidence for mechanistic hypotheses of IDIAG and new hypotheses are explored.
  
  
  CONCLUSIONS
  The characteristics of IDIAG are most consistent with an immune mechanism. Where genetic studies have been done, the genes associated with an increased risk of IDIAG are either human leukocyte antigen genes or other genes associated with the immune response, which provides further evidence for an immune mechanism. There is evidence that the immune response leading to most IDRs is triggered by reactive metabolites of the offending drug, and most drugs that are associated with IDIAG are either known to be oxidized to a reactive metabolite by neutrophils or have a functional group that has the potential to be easily oxidized to a reactive metabolite. There is new evidence that drugs that cause IDRs including IDIAG can activate inflammasomes. Thus, the ability of a drug to be oxidized to a reactive metabolite by neutrophils and to activate inflammasomes may be useful biomarkers to predict IDIAG risk.
authors.affiliation: University of Toronto, Pharmaceutical Sciences , 144 College Street, Toronto, Ontario, M5S3M2 , Canada.
authors.forename: Alexander
authors.initials: A
authors.lastname: Johnston
authors.forename: Jack
authors.initials: J
authors.lastname: Uetrecht
mesh_terms: D000380:Agranulocytosis / Q000139:chemically induced* / Q000276:immunology / Q000473:pathology; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D064420:Drug-Related Side Effects and Adverse Reactions / Q000276:immunology*; D006680:HLA Antigens / Q000235:genetics; D006801:Humans; D058847:Inflammasomes / Q000187:drug effects / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism*; D010084:Oxidation-Reduction
chemical_list: D015415:Biomarkers; D006680:HLA Antigens; D058847:Inflammasomes
keywords: adverse drug reactions; danger hypothesis; drug-induced agranulocytosis; hapten hypothesis; idiosyncratic drug reactions; inflammasome; myeloperoxidase; neutrophil; reactive metabolites