Carbamazepine-mediated adverse drug reactions: CBZ-10,11-epoxide but not 
carbamazepine induces the alteration of peptides presented by HLA-B*15:02.

Simper, G. S.; Ho, G. G. T.; Celik, A. A.; Huyton, T.; Kuhn, J.; Kunze-Schumacher, H.; Blasczyk, R.; Bade-Döding, C.

doi:10.1155/2018/5086503

Item

ITEM ACTIONSEXPORT

Add to Basket

Local TagsRelease HistoryDetailsSummary

Released

Journal Article

Carbamazepine-mediated adverse drug reactions: CBZ-10,11-epoxide but not carbamazepine induces the alteration of peptides presented by HLA-B*15:02.

MPS-Authors

/persons/resource/persons221173

Huyton, T.
Department of Cellular Logistics, MPI for Biophysical Chemistry, Max Planck Society;

External Resource

No external resources are shared

Fulltext (restricted access)

There are currently no full texts shared for your IP range.

Fulltext (public)

3002355.pdf
(Publisher version), 5MB

Supplementary Material (public)

3002355_Suppl.docx
(Supplementary material), 203KB

Citation

Simper, G. S., Ho, G. G. T., Celik, A. A., Huyton, T., Kuhn, J., Kunze-Schumacher, H., et al. (2018). Carbamazepine-mediated adverse drug reactions: CBZ-10,11-epoxide but not carbamazepine induces the alteration of peptides presented by HLA-B*15:02. Journal of Immunology Research, 2018: 5086503. doi:10.1155/2018/5086503.

Cite as: https://hdl.handle.net/21.11116/0000-0002-50D7-1

Abstract

Among patients treated with the anticonvulsive and psychotropic drug carbamazepine (CBZ), approximately 10% develop severe and life-threatening adverse drug reactions. These immunological conditions are resolved upon withdrawal of the medicament, suggesting that the drug does not manifest in the body in long term. The HLA allele B*15:02 has been described to be a genomic biomarker for CBZ-mediated immune reactions. It is not well understood if the immune reactions are triggered by the original drug or by its metabolite carbamazepine-10,11-epoxide (EPX) and how the interaction between the drug and the distinct HLA molecule occurs. Genetically engineered human B-lymphoblastoid cells expressing soluble HLA-B*15:02 molecules were treated with the drug or its metabolite. Functional pHLA complexes were purified; peptides were eluted and sequenced. Applying mass spectrometric analysis, CBZ and EPX were monitored by analyzing the heavy chain and peptide fractions separately for the presence of the drug. This method enabled the detection of the drug in a biological situation post-pHLA assembly. Both drugs were bound to the HLA-B*15:02 heavy chain; however, solely EPX altered the peptide-binding motif of B*15:02-restricted peptides. This observation could be explained through structural insight; EPX binds to the peptide-binding region and alters the biochemical features of the F pocket and thus the peptide motif. Understanding the nature of immunogenic interactions between CBZ and EPX with the HLA immune complex will guide towards effective and safe medications.