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Simper GS, Gräser LS, Celik AA, et al. The Mechanistic Differences in HLA-Associated Carbamazepine Hypersensitivity. Pharmaceutics. 2019;11(10)doi: 10.3390/pharmaceutics11100536.
Simper, G. S., Gräser, L. S., Celik, A. A., Kuhn, J., Kunze-Schumacher, H., Hò, G. T., Blasczyk, R., Pich, A., & Bade-Doeding, C. (2019). The Mechanistic Differences in HLA-Associated Carbamazepine Hypersensitivity. Pharmaceutics, 11(10), . https://doi.org/10.3390/pharmaceutics11100536
Simper, Gwendolin S, et al. "The Mechanistic Differences in HLA-Associated Carbamazepine Hypersensitivity." Pharmaceutics vol. 11,10 (2019). doi: https://doi.org/10.3390/pharmaceutics11100536
Simper GS, Gräser LS, Celik AA, Kuhn J, Kunze-Schumacher H, Hò GT, Blasczyk R, Pich A, Bade-Doeding C. The Mechanistic Differences in HLA-Associated Carbamazepine Hypersensitivity. Pharmaceutics. 2019 Oct 15;11(10). doi: 10.3390/pharmaceutics11100536. PMID: 31618895; PMCID: PMC6835980.
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Pharmaceutics. 2019 Oct 15;11(10). doi: 10.3390/pharmaceutics11100536.

The Mechanistic Differences in HLA-Associated Carbamazepine Hypersensitivity.

Pharmaceutics

Gwendolin S Simper, Lareen S Gräser, Alexander A Celik, Joachim Kuhn, Heike Kunze-Schumacher, Gia-Gia T Hò, Rainer Blasczyk, Andreas Pich, Christina Bade-Doeding

Affiliations

  1. Institute for Transfusion Medicine, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. [email protected].
  2. Institute for Transfusion Medicine, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. [email protected].
  3. Institute for Transfusion Medicine, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. [email protected].
  4. Institute for Laboratory and Transfusion Medicine, Heart and Diabetes Center North Rhine-Westphalia, Ruhr University Bochum, Georgstraße 11, 32545 Bad Oeynhausen, Germany. [email protected].
  5. Institute for Transfusion Medicine, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. [email protected].
  6. Institute for Transfusion Medicine, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. [email protected].
  7. Institute for Transfusion Medicine, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. [email protected].
  8. Institute of Toxicology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. [email protected].
  9. Institute for Transfusion Medicine, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. [email protected].

PMID: 31618895 PMCID: PMC6835980 DOI: 10.3390/pharmaceutics11100536

Abstract

Drug hypersensitivity reactions that resemble acute immune reactions are linked to certain human leucocyte antigen (HLA) alleles. Severe and life-threatening Stevens Johnson Syndrome and Toxic Epidermal Necrolysis following treatment with the antiepileptic and psychotropic drug Carbamazepine are associated with HLA-B*15:02; whereas carriers of HLA-A*31:01 develop milder symptoms. It is not understood how these immunogenic differences emerge genotype-specific. For HLA-B*15:02 an altered peptide presentation has been described following exposure to the main metabolite of carbamazepine that is binding to certain amino acids in the F pocket of the HLA molecule. The difference in the molecular mechanism of these diseases has not been comprehensively analyzed, yet; and is addressed in this study. Soluble HLA-technology was utilized to examine peptide presentation of HLA-A*31:01 in presence and absence of carbamazepine and its main metabolite and to examine the mode of peptide loading. Proteome analysis of drug-treated and untreated cells was performed. Alterations in sA*31:01-presented peptides after treatment with carbamazepine revealed different half-life times of peptide-HLA- or peptide-drug-HLA complexes. Together with observed changes in the proteome elicited through carbamazepine or its metabolite these results illustrate the mechanistic differences in carbamazepine hypersensitivity for HLA-A*31:01 or B*15:02 patients and constitute the bridge between pharmacology and pharmacogenetics for personalized therapeutics.

Keywords: HLA-A*31:01; HLA-B*15:02; adverse drug reaction; carbamazepine; carbamazepine-10,11-epoxide; proteome

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