The roles of drug metabolism in the pathogenesis of T-cell-mediated drug hypersensitivity.
OBJECTIVE
The purpose of this review is to highlight recent studies on drug metabolism in T-cell-mediated reactions. Although the hapten theory and the danger hypothesis imply an important role of reactive metabolites in the pathogenesis of drug hypersensitivity, the more recent pi concept gives the central role to the parent drug. It is therefore important to have a broad vision on data supporting each theory to understand the potential role(s) of drug metabolism in T-cell-mediated hypersensitivity.


RESULTS
Reactive metabolites have been identified for most drugs associated with hypersensitivity. Recent studies have further characterized drug metabolism outside the liver, in key tissues such as the skin and immune cells. Localized drug metabolism is associated with oxidative stress, adduct formation and toxicity creating danger signals for antigen presenting cells, influencing whether a drug antigen will induce tolerance or immunity.


CONCLUSIONS
The involvement of metabolic drug activation in the initiation and propagation of hypersensitivity is intriguing since metabolites are generated in different quantities throughout the body, can be directly or indirectly toxic to cells, might stimulate innate immunity, and can bind to protein to generate neoantigens for cellular and humoral responses.
Lavergne
Sidonie Nelly
SN
Department of Pharmacology, School of Biomedical Sciences, University of Liverpool, Liverpool, UK. sidolavergne@hotmail.com
Park
Brian Kevin
BK
Naisbitt
Dean John
DJ
D000818:Animals; D001711:Biotransformation / Q000276:immunology; D004342:Drug Hypersensitivity / Q000209:etiology* / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D007108:Immune Tolerance; D007111:Immunity, Cellular / Q000187:drug effects*; D018384:Oxidative Stress / Q000276:immunology; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000378:metabolism*; D010597:Pharmacogenetics; D017382:Reactive Oxygen Species / Q000009:adverse effects / Q000276:immunology; D037182:T-Cell Antigen Receptor Specificity / Q000187:drug effects; D013601:T-Lymphocytes / Q000166:cytology* / Q000378:metabolism
D004364:Pharmaceutical Preparations; D017382:Reactive Oxygen Species