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Alkylated epidermal creatine kinase as a biomarker for sulfur mustard exposure: comparison to adducts of albumin and DNA in an in vivo rat study.

Authors
  • Steinritz, Dirk1, 2, 3
  • Lüling, Robin4, 5
  • Siegert, Markus4, 6
  • Herbert, Julia4, 7
  • Mückter, Harald5
  • Taeger, Christian D8
  • Gudermann, Thomas5
  • Dietrich, Alexander5
  • Thiermann, Horst4
  • John, Harald4
  • 1 Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstraße 11, 80937, Munich, Germany. [email protected] , (Germany)
  • 2 Walther-Straub-Institute of Pharmacology and Toxicology, Ludwig-Maximilians-Universität Munich (LMU), Goethestraße 33 / Nussbaumstraße 26, 80366, Munich, Germany. [email protected] , (Germany)
  • 3 Bundeswehr Medical Service Academy, Ingolstädter Straße 240, 80939, Munich, Germany. [email protected] , (Germany)
  • 4 Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstraße 11, 80937, Munich, Germany. , (Germany)
  • 5 Walther-Straub-Institute of Pharmacology and Toxicology, Ludwig-Maximilians-Universität Munich (LMU), Goethestraße 33 / Nussbaumstraße 26, 80366, Munich, Germany. , (Germany)
  • 6 Proteros Biostrucures GmbH, Bunsenstraße 7a, 82152, Planegg, Germany. , (Germany)
  • 7 Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ, USA.
  • 8 Department of Plastic-, Hand- and Reconstructive Surgery, University Hospital Regensburg, Franz-Josef-Strauß-Allee 11, 93053, Regensburg, Germany. , (Germany)
Type
Published Article
Journal
Archives of Toxicology
Publisher
Springer-Verlag
Publication Date
Apr 01, 2021
Volume
95
Issue
4
Pages
1323–1333
Identifiers
DOI: 10.1007/s00204-021-03005-3
PMID: 33635393
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Sulfur mustard (SM) is a chemical warfare agent which use is banned under international law and that has been used recently in Northern Iraq and Syria by the so-called Islamic State. SM induces the alkylation of endogenous proteins like albumin and hemoglobin thus forming covalent adducts that are targeted by bioanalytical methods for the verification of systemic poisoning. We herein report a novel biomarker, namely creatine kinase (CK) B-type, suitable as a local biomarker for SM exposure on the skin. Human and rat skin were proven to contain CK B-type by Western blot analysis. Following exposure to SM ex vivo, the CK-adduct was extracted from homogenates by immunomagnetic separation and proteolyzed afterwards. The cysteine residue Cys282 was found to be alkylated by the SM-specific hydroxyethylthioethyl (HETE)-moiety detected as the biomarker tetrapeptide TC(-HETE)PS. A selective and sensitive micro liquid chromatography-electrospray ionization high-resolution tandem-mass spectrometry (µLC-ESI MS/HRMS) method was developed to monitor local CK-adducts in an in vivo study with rats percutaneously exposed to SM. CK-adduct formation was compared to already established DNA- and systemic albumin biomarkers. CK- and DNA-adducts were successfully detected in biopsies of exposed rat skin as well as albumin-adducts in plasma. Relative biomarker concentrations make the CK-adduct highly appropriate as a local dermal biomarker. In summary, CK or rather Cys282 in CK B-type was identified as a new, additional dermal target of local SM exposures. To our knowledge, it is also the first time that HETE-albumin adducts, and HETE-DNA adducts were monitored simultaneously in an in vivo animal study.

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