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 mM 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 mM cadaverine. In 90% EDTA plasma, the IC50 concentrations were 2–3 mM using 0.9 mM and 0.18 mM 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.
Original language | English |
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Pages (from-to) | 113-122 |
Number of pages | 10 |
Journal | Journal of Pharmacology and Experimental Therapeutics |
Volume | 382 |
Issue number | 2 |
DOIs | |
Publication status | Published - 1 Aug 2022 |
MoE publication type | A1 Journal article-refereed |
Keywords
- Amine Oxidase (Copper-Containing)/chemistry
- Anaphylaxis
- Benzamidines
- Diminazene
- Edetic Acid
- Guanidines
- Histamine
- Humans