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Research ArticleToxicology

Nafamostat is a Potent Human Diamine Oxidase Inhibitor Possibly Augmenting Hypersensitivity Reactions during Nafamostat Administration

Thomas Boehm, Marion Alix, Karin Petroczi, Serhii Vakal, Elisabeth Gludovacz, Nicole Borth, Tiina A. Salminen and Bernd Jilma
Journal of Pharmacology and Experimental Therapeutics August 2022, 382 (2) 113-122; DOI: https://doi.org/10.1124/jpet.122.001248
Thomas Boehm
Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria (T.B., K.P., E.G., B.J.); Structural Bioinformatics Laboratory, Biochemistry, Faculty of Science and Engineering (M.A., S.V., T.A.S.), and InFLAMES Research Flagship Center (M.A., S.V., T.A.S.), Åbo Akademi University, Turku, Finland; and Department of Biotechnology, University of Natural Resources and Life Sciences, Vienna, Austria (E.G., N.B.)
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Marion Alix
Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria (T.B., K.P., E.G., B.J.); Structural Bioinformatics Laboratory, Biochemistry, Faculty of Science and Engineering (M.A., S.V., T.A.S.), and InFLAMES Research Flagship Center (M.A., S.V., T.A.S.), Åbo Akademi University, Turku, Finland; and Department of Biotechnology, University of Natural Resources and Life Sciences, Vienna, Austria (E.G., N.B.)
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Karin Petroczi
Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria (T.B., K.P., E.G., B.J.); Structural Bioinformatics Laboratory, Biochemistry, Faculty of Science and Engineering (M.A., S.V., T.A.S.), and InFLAMES Research Flagship Center (M.A., S.V., T.A.S.), Åbo Akademi University, Turku, Finland; and Department of Biotechnology, University of Natural Resources and Life Sciences, Vienna, Austria (E.G., N.B.)
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Serhii Vakal
Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria (T.B., K.P., E.G., B.J.); Structural Bioinformatics Laboratory, Biochemistry, Faculty of Science and Engineering (M.A., S.V., T.A.S.), and InFLAMES Research Flagship Center (M.A., S.V., T.A.S.), Åbo Akademi University, Turku, Finland; and Department of Biotechnology, University of Natural Resources and Life Sciences, Vienna, Austria (E.G., N.B.)
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Elisabeth Gludovacz
Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria (T.B., K.P., E.G., B.J.); Structural Bioinformatics Laboratory, Biochemistry, Faculty of Science and Engineering (M.A., S.V., T.A.S.), and InFLAMES Research Flagship Center (M.A., S.V., T.A.S.), Åbo Akademi University, Turku, Finland; and Department of Biotechnology, University of Natural Resources and Life Sciences, Vienna, Austria (E.G., N.B.)
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Nicole Borth
Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria (T.B., K.P., E.G., B.J.); Structural Bioinformatics Laboratory, Biochemistry, Faculty of Science and Engineering (M.A., S.V., T.A.S.), and InFLAMES Research Flagship Center (M.A., S.V., T.A.S.), Åbo Akademi University, Turku, Finland; and Department of Biotechnology, University of Natural Resources and Life Sciences, Vienna, Austria (E.G., N.B.)
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Tiina A. Salminen
Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria (T.B., K.P., E.G., B.J.); Structural Bioinformatics Laboratory, Biochemistry, Faculty of Science and Engineering (M.A., S.V., T.A.S.), and InFLAMES Research Flagship Center (M.A., S.V., T.A.S.), Åbo Akademi University, Turku, Finland; and Department of Biotechnology, University of Natural Resources and Life Sciences, Vienna, Austria (E.G., N.B.)
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Bernd Jilma
Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria (T.B., K.P., E.G., B.J.); Structural Bioinformatics Laboratory, Biochemistry, Faculty of Science and Engineering (M.A., S.V., T.A.S.), and InFLAMES Research Flagship Center (M.A., S.V., T.A.S.), Åbo Akademi University, Turku, Finland; and Department of Biotechnology, University of Natural Resources and Life Sciences, Vienna, Austria (E.G., N.B.)
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Abstract

Nafamostat is an approved short-acting serine protease inhibitor. However, its administration is also associated with anaphylactic reactions. One mechanism to augment hypersensitivity reactions could be inhibition of diamine oxidase (DAO). The chemical structure of nafamostat is related to the potent DAO inhibitors pentamidine and diminazene. Therefore, we tested whether nafamostat is a human DAO inhibitor. Using different activity assays, nafamostat reversibly inhibited recombinant human DAO with an IC50 of 300–400 nM using 200 µM substrate concentrations. The Ki of nafamostat for the inhibition of putrescine and histamine deamination is 27 nM and 138 nM, respectively For both substrates, nafamostat is a mixed mode inhibitor with P values of <0.01 compared with other inhibition types. Using 80–90% EDTA plasma, the IC50 of nafamostat inhibition was approximately 360 nM using 20 µM cadaverine. In 90% EDTA plasma, the IC50 concentrations were 2–3 µM using 0.9 µM and 0.18 µM histamine as substrate. In silico modeling showed a high overlap compared with published diminazene crystallography data, with a preferred orientation of the guanidine group toward topaquinone. In conclusion, nafamostat is a potent human DAO inhibitor and might increase severity of anaphylactic reaction by interfering with DAO-mediated extracellular histamine degradation.

SIGNIFICANCE STATEMENT Treatment with the short-acting anticoagulant nafamostat during hemodialysis, leukocytapheresis, extracorporeal membrane oxygenator procedures, and disseminated intravascular coagulation is associated with severe anaphylaxis in humans. Histamine is a central mediator in anaphylaxis. Potent inhibition of the only extracellularly histamine-degrading enzyme diamine oxidase could augment anaphylaxis reactions during nafamostat treatment.

Footnotes

    • Received April 1, 2022.
    • Accepted May 16, 2022.
  • This work was supported by the InFLAMES Flagship Program of the Academy of Finland [decision number: 337530] and the Sigrid Juselius foundation.

  • https://doi.org/10.1124/jpet.122.001248.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 382 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 382, Issue 2
1 Aug 2022
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Research ArticleToxicology

Nafamostat is a Potent Human Diamine Oxidase Inhibitor

Thomas Boehm, Marion Alix, Karin Petroczi, Serhii Vakal, Elisabeth Gludovacz, Nicole Borth, Tiina A. Salminen and Bernd Jilma
Journal of Pharmacology and Experimental Therapeutics August 1, 2022, 382 (2) 113-122; DOI: https://doi.org/10.1124/jpet.122.001248

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Research ArticleToxicology

Nafamostat is a Potent Human Diamine Oxidase Inhibitor

Thomas Boehm, Marion Alix, Karin Petroczi, Serhii Vakal, Elisabeth Gludovacz, Nicole Borth, Tiina A. Salminen and Bernd Jilma
Journal of Pharmacology and Experimental Therapeutics August 1, 2022, 382 (2) 113-122; DOI: https://doi.org/10.1124/jpet.122.001248
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