Diamine oxidase knockout mice are not hypersensitive to orally or subcutaneously administered histamine. 2022

Matthias Karer, and Marlene Rager-Resch, and Teresa Haider, and Karin Petroczi, and Elisabeth Gludovacz, and Nicole Borth, and Bernd Jilma, and Thomas Boehm
Department of Clinical Pharmacology, Medical University Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.

OBJECTIVE To evaluate the contribution of endogenous diamine oxidase (DAO) in the inactivation of exogenous histamine, to find a mouse strain with increased histamine sensitivity and to test the efficacy of rhDAO in a histamine challenge model. METHODS Diamine oxidase knockout (KO) mice were challenged with orally and subcutaneously administered histamine in combination with the β-adrenergic blocker propranolol, with the two histamine-N-methyltransferase (HNMT) inhibitors metoprine and tacrine, with folic acid to mimic acute kidney injury and treated with recombinant human DAO. Core body temperature was measured using a subcutaneously implanted microchip and histamine plasma levels were quantified using a homogeneous time resolved fluorescence assay. RESULTS Core body temperature and plasma histamine levels were not significantly different between wild type (WT) and DAO KO mice after oral and subcutaneous histamine challenge with and without acute kidney injury or administration of HNMT inhibitors. Treatment with recombinant human DAO reduced the mean area under the curve (AUC) for core body temperature loss by 63% (p = 0.002) and the clinical score by 88% (p < 0.001). The AUC of the histamine concentration was reduced by 81%. CONCLUSIONS Inactivation of exogenous histamine is not driven by enzymatic degradation and kidney filtration. Treatment with recombinant human DAO strongly reduced histamine-induced core body temperature loss, histamine concentrations and prevented the development of severe clinical symptoms.

UI MeSH Term Description Entries
D006631 Amine Oxidase (Copper-Containing) A group of enzymes including those oxidizing primary monoamines, diamines, and histamine. They are copper proteins, and, as their action depends on a carbonyl group, they are sensitive to inhibition by semicarbazide. Diamine Oxidase,Histaminase,Amine Oxidase, Copper-Containing,Copper Amine Oxidase,Diaminobenzidine Oxidase,Semicarbazide-Sensitive Amine Oxidase,Xylylene Diamine Oxidase,Amine Oxidase, Copper,Amine Oxidase, Copper Containing,Amine Oxidase, Semicarbazide-Sensitive,Copper-Containing Amine Oxidase,Diamine Oxidase, Xylylene,Oxidase, Copper Amine,Oxidase, Copper-Containing Amine,Oxidase, Diamine,Oxidase, Diaminobenzidine,Oxidase, Semicarbazide-Sensitive Amine,Oxidase, Xylylene Diamine,Semicarbazide Sensitive Amine Oxidase
D006632 Histamine An amine derived by enzymatic decarboxylation of HISTIDINE. It is a powerful stimulant of gastric secretion, a constrictor of bronchial smooth muscle, a vasodilator, and also a centrally acting neurotransmitter. Ceplene,Histamine Dihydrochloride,Histamine Hydrochloride,Peremin
D006637 Histamine N-Methyltransferase An enzyme that catalyzes the transfer of a methyl group from S-adenosylmethionine to histamine, forming N-methylhistamine, the major metabolite of histamine in man. EC 2.1.1.8. Histamine Methyltransferase,Histamine N Methyltransferase,Methyltransferase, Histamine,N-Methyltransferase, Histamine
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D051379 Mice The common name for the genus Mus. Mice, House,Mus,Mus musculus,Mice, Laboratory,Mouse,Mouse, House,Mouse, Laboratory,Mouse, Swiss,Mus domesticus,Mus musculus domesticus,Swiss Mice,House Mice,House Mouse,Laboratory Mice,Laboratory Mouse,Mice, Swiss,Swiss Mouse,domesticus, Mus musculus
D058186 Acute Kidney Injury Abrupt reduction in kidney function. Acute kidney injury encompasses the entire spectrum of the syndrome including acute kidney failure; ACUTE KIDNEY TUBULAR NECROSIS; and other less severe conditions. Acute Kidney Failure,Acute Kidney Insufficiency,Acute Renal Failure,Acute Renal Injury,Acute Renal Insufficiency,Kidney Failure, Acute,Kidney Insufficiency, Acute,Renal Failure, Acute,Renal Insufficiency, Acute,Acute Kidney Failures,Acute Kidney Injuries,Acute Kidney Insufficiencies,Acute Renal Failures,Acute Renal Injuries,Acute Renal Insufficiencies,Kidney Failures, Acute,Kidney Injuries, Acute,Kidney Injury, Acute,Kidney Insufficiencies, Acute,Renal Failures, Acute,Renal Injuries, Acute,Renal Injury, Acute,Renal Insufficiencies, Acute
D018345 Mice, Knockout Strains of mice in which certain GENES of their GENOMES have been disrupted, or "knocked-out". To produce knockouts, using RECOMBINANT DNA technology, the normal DNA sequence of the gene being studied is altered to prevent synthesis of a normal gene product. Cloned cells in which this DNA alteration is successful are then injected into mouse EMBRYOS to produce chimeric mice. The chimeric mice are then bred to yield a strain in which all the cells of the mouse contain the disrupted gene. Knockout mice are used as EXPERIMENTAL ANIMAL MODELS for diseases (DISEASE MODELS, ANIMAL) and to clarify the functions of the genes. Knockout Mice,Mice, Knock-out,Mouse, Knockout,Knock-out Mice,Knockout Mouse,Mice, Knock out

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