Diamine Oxidase Knockout Mice Are Not Hypersensitive To Orally Or Subcutaneously Administered Histamine

Abstract

1. 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.

2. 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 methoprene 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.

3. 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%.

4. Conclusions

The 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, and histamine concentrations and prevented the development of severe clinical symptoms.

Keywords

Amine oxidase (copper-containing) · Histamine N-methyltransferase · Acute kidney injury · Metabolism · Tacrine · Metoprine · Body temperature

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Introduction

More than 95% of all histamine in humans is stored in mast cells and basophils. The same is likely to be true for many mammals. In humans, mast cell densities are highest in the gastrointestinal tract, the skin, and the lungs [1], and consequently, these organs show histamine-induced symptoms in diseases with clear involvement of mast cell activation. The local interstitial concentrations of histamine after acute degranulation can reach 10–1000 µMs [2, 3, see Online Resources]. In humans, similarly to dogs and pigs, normal plasma histamine concentrations are below 1 ng/ml (9 nM) and symptoms start to develop at a few nanograms per milliliter [4–7]. Significant hypotension with increased heart rate can be measured from 5 ng/ml and when levels rise above 10 ng/ml the development of bronchospasm, cardiac arrhythmias, severe hypotension, and coronary spasm can lead to life-threatening multi-system dysfunction [8, 9]. Histamine is not only involved in vasodilation, vascular permeability increases, hypoxia, and the development of vascular edema but also demonstrates pro-inflammatory involvement influencing the adaptive immune system via recruitment, maturation, and activation of immune effector cells. Additionally, it plays a role in the innate immune system by interacting with dendritic cells, natural killer cells, and granulocytes [10, 11].

Baseline histamine concentrations in mice and rats are between 20 and 100 ng/ml when measured using reliable methods and are therefore many times higher than those found in humans [6, 7]. It is not clear whether these high histamine levels play any physiological role. Rodents are notoriously resistant to histamine with lethal doses of 50% (LD50) in different mouse strains of 3000–4000 and 400–500 mg/ kg after oral and intravenous administration, respectively [12, 13]. The peak plasma histamine concentration after a bolus administration of 400 mg/kg in a 20 g mouse would be approximately 8 mg/ml assuming a plasma volume of 1 ml. When anaphylaxis was induced in humans via a controlled wasp sting challenge, histamine concentrations of 140 ng/ ml were associated with severe life-threatening hypotension [14]. How is histamine metabolized and inactivated?

Histamine shows 13% mean plasma protein binding and is freely filtrated in the kidneys [15]. The glomerular filtration rate (GFR) can theoretically contribute about 15–20% to the half-life of 3–4 min found in healthy volunteers [5, see Online Resources]. At a normal GFR of 100 ml/min and a plasma volume of 3000 ml the half-life of histamine would be 20 min. In mice, a normal GFR of 10 µl/min/g would result in a histamine half-life of 3 min [16, see Online Resources]. Nevertheless, histamine shows a high extraction rate in the kidney, exceeding rates based on the GFR, and this extraction is ascribed to uptake and reabsorption into the proximal tubular cells via organic cation transporter 2 (OCT2), followed by enzymatic inactivation [17, see below]. In humans, less than 1% of the injected radioactive histamine was found in urine within the first 6 h [18]. The low rate of histamine excretion in humans, which is also seen in dogs and cats, has been confirmed by others [19]. In mice and rat tissues, more than 50% of the injected radioactivity is found in the kidneys, and less than 2% as histamine 30 min after intravenous administration [20]. The kidneys were also the organ with the highest radioactivity after high-dose histamine administration in rats [21]. The OCT2 transporter is highly expressed in human and rodent kidneys and might be responsible for both the extraction of histamine from the plasma compartment and the reabsorption of histamine in the primary urine filtrate into proximal tubular cells [22, see below].

Rapid transport of extracellular histamine from the interstitial fluid after release from mast cells or plasma to other compartments away from the endothelial cells would be another possibility to inactivate histamine. This might inhibit the induction of severe hypotension and vascular leakage mediated via endothelial nitric oxide synthase (NOS) signaling and binding to histamine receptors [23–25]. However, no in vivo animal data studying the transport rates of histamine from the systemic circulation into endothelial or parenchymal cells are available. In several in vitro studies, histamine is transported bidirectionally using the low-affinity, high-capacity OCT2, and OCT3 [22, 26, 27]. Histamine is an excellent substrate for the rat OCT2 and OCT3 transporter, showing higher transport efficiencies compared to the equivalent human OCT proteins [26].

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When low concentrations of radioactive histamine are used in mice, methylation via histamine-N-methyltransferase (HNMT) seems to be the major route of inactivation. Challenging mice with higher doses of histamine, however, shifts metabolism to imidazole acetic acid (IMAA) and riboside conjugates, with only a small amount of methylated derivatives detected [28–30]. The fivefold increased baseline serum histamine concentrations in the HNMT knock-out mice support these data [31]. Imidazoleacetic acid is generated via histamine oxidation by diamine oxidase (DAO) releasing imidazole acetaldehyde, which is converted to IMAA and riboside derivatives, mainly in the liver. Oxidation of histamine via DAO appears to play a greater role in histamine catabolism after oral challenge in mice, which is not surprising considering that in mice DAO expression is high only in the gastrointestinal tract [30]. When an oral histamine challenge is performed in humans oxidative deamination via DAO is the dominant catabolic pathway with IMAA as the main urinary metabolite [18].

Diamine oxidase is a copper-containing amine oxidase and one of two enzymes capable of inactivating histamine [32]. In selected tissues, mainly the small intestine and the kidney proximal tubular cells, DAO is located in ill-defined intracellular granular structures and extracellularly bound to heparan sulfate proteoglycans, whereas HNMT is present only in the cytoplasm [33, 34]. The expression of HNMT is widespread throughout the body, with higher levels found in the central nervous system, bladder, heart, kidneys, liver, lung, and in adipose tissue.

After DAO inhibition using aminoguanidine, sheep showed extensive clinical symptoms of histamine toxicity after oral histamine challenge compared to controls without aminoguanidine pre-treatment [35]. A similar experiment in pigs resulted in severe morbidity and mortality in animals pre-treated with aminoguanidine and subsequently challenged with oral histamine [36]. Median plasma histamine concentrations increased 20-fold in pigs with DAO inhibition. Treatment of rats with aminoguanidine followed by oral histamine challenge increased urinary IMAA and reduced histamine concentration by approximately fivefold [37]. These data indicated that DAO plays a crucial role in the degradation of exogenous orally administered histamine.

In mice, aminoguanidine treatment strongly increased histamine concentrations in the intestine after intravenous histamine challenge [30]. However, aminoguanidine is not a specific DAO inhibitor, but blocks also all three NOS enzymes and appears to block the transport of blood histamine into tissues [38, 39]. Administration of burimamide, a histamine receptor 2 antagonist, showed detrimental effects with increased mortality in a circulatory shock model in rats. However, at the same time, it was published that burimamide is a potent DAO inhibitor [40, 41]. In dogs, burimamide caused a 17-fold increase in mean plasma histamine concentration and a strong reduction in the mean arterial pressure [42]. The effect was believed to be due to possible mast cell activation.

Similarly, the role of HNMT was studied using methylhistamine as an HNMT inhibitor, but methyl-histamine is also an excellent substrate for DAO [43]. Amodiaquine and quinacrine are potent HNMT inhibitors [44–46] but also inhibit DAO with an inhibitory concentration of 50% (IC50) of approximately 500 nM [47, unpublished data]. Therefore, data derived using inhibitors, which are often used at high concentrations, must be interpreted with caution, because known and unknown off-target effects are likely and can significantly distort the physiological relevance of in vivo studies.

Metabolic studies might provide some indication of the importance of the two enzymes in the degradation of histamine, but catabolism of histamine could be decoupled from physiological or pathophysiological effects. The compartmental histamine concentrations could be critical and metabolism might be downstream.

We, therefore, decided to use the DAO knock-out (KO) mouse to study the role of DAO in the degradation of exogenous histamine. A second key aim was to develop a mouse model with increased histamine sensitivity to enable us to better study the role of histamine in various genetic mutant strains and to test the efficacy of recombinant human DAO in a histamine challenge model.

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Material and methods

Animal models

Experiments were performed using 10–18-weeks-old C57BL6/J Aoc1tm1b(EUCOMM)Hmgu (DAO) KO mice and wild-type (WT) littermates. Heterozygous embryos were provided by the European Mouse Mutant Archive, Munich, Germany, and implanted into pseudopregnant C57BL6/N mice. Heterozygous C57BL6/J offspring mice were confirmed using PCR (see Online Resources) and further used to breed DAO KO mice at the Division of Biomedical Research, Medical University of Vienna, by the animal protocol GZ 66.009/0160-WF/V/3b/2016. All animal experiments were conducted according to protocol GZ 66.009/0258- V/3b/2019. Experimental protocols were approved by the Austrian Ministry of Education, Science, and Research. Animals were kept at a 12:12 h day–night cycle at 22 °C with water and food ad libitum. For non-invasive temperature measurements, a transponder (IPTT-300, BioMedic Data Systems Inc., USA) was implanted subcutaneously 2 weeks before the experiment using short isoflurane anesthesia. The transponder measures the temperature three times within one second and the mean of these measurements is recorded from the outside of the cage using a reader. This mean value is then used for further calculations. These subcutaneous transponders are used to avoid excessive manipulation of animals and to prevent injury from repeated insertion of rectal temperature probes [48]. In several animal species including rodents, histamine administration has been shown to lower body temperature and is considered the state-of-the-art readout for the effects of histamine [49, 50]. During the observational period, clinical symptoms were evaluated by an experienced veterinarian according to a published hypersensitivity score [51]. The score ranged from 0 (no symptoms) to 1 (rubbing and scratching of head and nose), 2 (reduced activity with increased respiratory rate and/or reduced activity, puffiness around mouth and eyes), 3 (labored respiration, cyanosis around tail and mouth, wheezing) and 4 (no activity after prodding or tremor and convulsion). A score of 5 denoted death. All challenge experiments were started between 9:00 and 11:00 am to avoid time-of-day-dependent variations [52].

General experimental setup

All substances were applied in a volume of 5 ml/kg. Propranolol (P0884, Sigma-Aldrich, Austria) was dissolved in saline and applied intraperitoneally (i.p.) at a concentration of 2 mg/kg 20 min before the histamine challenge to increase sensitivity for histamine [53]. Histamine dihydrochloride (H7250, Sigma-Aldrich, Austria) was dissolved in double distilled (dd) H2O and further diluted in saline. All stated histamine concentrations refer to the histamine base (111.15 Dalton).

1. Oral and subcutaneous administration of histamine

Mice were fasted for 60 min in total. After 40 min of fasting, propranolol was administered and 20 min later histamine was applied at a concentration of 30 mg/kg per os (p.o.) using oral gavage. For the subcutaneous (s.c.) challenge model mice either received histamine at a concentration of 50 mg/kg without propranolol or 5 mg/kg with propranolol. For the determination of plasma histamine concentrations a subset of mice was anesthetized at different time points after the histamine challenge using 10 mg/kg xylazine and 100 mg/kg ketamine. Citrate plasma was collected from anesthetized mice using cardiac puncture. One to five mice were used per time point and genotype.

2. Concomitant histamine‑N‑methyltransferase (HNMT) inhibition

Metoprine (M338835, Toronto Research Chemicals, Canada) was dissolved in 10% lactic acid (L1875, Sigma-Aldrich, Austria), further diluted in saline and administered i.p. at 3 mg/kg 1 h before challenge with 5 mg/kg histamine. Tacrine (A79922, Sigma-Aldrich, Austria) was dissolved in ddH2O, further diluted in saline, and subsequently 10 mg/kg were applied i.p. 1 h before 25 mg/kg histamine s.c. and 2 mg/kg propranolol. A concentration of 2 mg/kg Tacrine i.p. was used in combination with 30 mg/kg histamine p.o. combined with 2 mg/kg propranolol.

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3. Induction of acute kidney injury (AKI) before histamine challenge

Folic acid (F7876, Sigma-Aldrich, Austria) was reconstituted in ddH2O, further diluted in saline, and applied i.p. at a concentration of 100 mg/kg 48 h before challenge with 5 mg/kg s.c. histamine and 2 mg/kg propranolol. The degree of acute kidney injury was estimated using plasma creatinine values. As a cut-off for inclusion, a creatinine value of at least threefold above the mean baseline value was used as described [54]. Baseline plasma creatinine concentrations of 0.11 and 0.17 mg/dl were measured in two mice and therefore an inclusion cut-off of>42 mg/dl was selected. Citrate plasma drawn via cardiac puncture was used to measure creatinine using a Cobas analyzer (Cobas C311 analyzer, Roche, Switzerland). To determine plasma histamine concentrations at different time points during s.c. histamine challenge with propranolol in acute kidney injury, two to four mice per time point were anesthetized, and citrate plasma was collected by heart puncture.

4. DAO rescue after histamine administration

Recombinant human (rh)DAO with a mutated heparin-binding motif (described in Gludovacz et al. [55]) was applied intravenously (i.v.) at a concentration of 4 mg/kg 40 min before application of 2 mg/kg propranolol and 60 min before challenge with 5 mg/kg s.c. histamine.

For the determination of histamine and DAO concentrations in plasma, mice were treated with either 4 mg/kg DAO or buffer i.v. 60 min before challenge with 5 mg/kg s.c. histamine combined with 2 mg/kg propranolol. The mice were anesthetized at different time points. Citrate plasma was collected using cardiac puncture from two to three mice per time point. Blood was collected in 3.8% sodium citrate and one part was immediately mixed with diminazene-aceturate (D7770, Sigma-Aldrich, Austria) resulting in a final concentration of 10 µM to inhibit histamine degradation by rhDAO.

Gene expression analysis

Tissue samples were shock-frozen in liquid nitrogen and total RNA was obtained using the FavorPrep Tissue Total RNA Kit (FATRK001, Favorgen, Taiwan) after tissue homogenization using lysing tubes (Lysing Matrix E, MP Biomedicals, Germany) on a Precellys 24 (Bertin Instruments, France). Reverse transcription was performed using the OneScript Plus cDNA synthesis kit (G236, ABM Good, Canada). For quantitative PCR BrightGreen Express 2× Mastermix (MasterMix-EL, ABM Good, Canada) was used. Exon spanning primers for DAO, HNMT, and histidine decarboxylase (HDC) were designed using Primer3 software (Online Resource Table 1). The housekeeping gene RPLP0 was used for normalization [56].

Western blot

For western blot analysis, frozen tissue samples were lysed in 20 mM K-phosphate buffer (pH 7.2) using lysing tubes (Lysing Matrix E tubes, MP Biomedicals, Germany) on a Precellys 24 (Bertin Instruments, France). Total protein concentration was determined using the QuantiPro BCA Assay Kit (QPBCA-1KT, Sigma, Austria). For Polyacrylamide gel electrophoresis 40 µg total protein and 40 ng recombinant murine DAO (provided by EG, University of Natural Resources and Life Sciences, Vienna, Austria, using methods described in [57]) were separated using a 12% Tris–glycine gel (4561043, Bio-Rad, USA). A monoclonal ABP1 antibody (sc-515908, Santa Cruz, USA) was used for DAO detection at a concentration of 0.4 µg/ml, and a monoclonal GAPDH antibody (2118, Cell Signal Technology, USA) was used as a loading control at a dilution of 1:2000. The monoclonal anti-mouse IgG-HRP antibody (A2554, Sigma Aldrich, Austria) and the anti-rabbit IgG-HRP antibody (A0545, Sigma Aldrich, Austria) were used as detection antibodies at a dilution of 1:40,000. Images were acquired using Clarity Max Western ECL Substrate (1705062, BioRad, USA) on a ChemiDoc Imaging System (17001401, Bio-Rad, USA).

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DAO activity measurement

Diamine oxidase activity of different tissue homogenates and inhibition by methoprene and tacrine were measured as described [58]. Frozen tissue samples were lysed in 20 mM K-phosphate buffer (pH 7.2) using lysing tubes on a Precellys 24. Total protein concentration was determined using the QuantiPro BCA Assay Kit and 500 µg total protein extracts of different tissues were incubated for 120 min with ortho-aminobenzaldehyde (oABA) and either ddH2O or 200 µM cadaverine (CAD). Delta-1-piperidine, the autocyclization product of CAD after deamination by DAO, condensates with oABA forming a fluorophore, which can be measured at EX440/30 and EM620/40 nm. For determination of DAO inhibition, rhDAO was preincubated with methoprene and tacrine at different concentrations for 30 min and measured as described above.

For determination of DAO activity, tissue homogenates with a protein concentration of 200 µg/ml were mixed with HRP (final concentration 1.2 µg/ml, P6782, Sigma-Aldrich, Austria) and aminoguanidine (final concentration 10 µM, 396494, Sigma-Aldrich, Austria) or K-phosphate buffer (pH 7.2) was added and incubated for 15 min at 37 °C. Amplex red™ (final concentration 100 µM, A12222, Thermo Scientific, USA) was added and reactions were started via the addition of 200 µM final putrescine concentration (51799, Sigma-Aldrich, Austria). Potassium phosphate buffer (pH 7.2) was used as a negative control. Samples were incubated at 37 °C and measured every 10 min for 120 min using EX550 and EM590 nm. The DAO-specific signal was calculated by subtracting samples with aminoguanidine, a potent and irreversible DAO inhibitor, from samples with K-phosphate buffer.

For plasma DAO activity measurements in mice receiving i.v. Rhoda a hybrid assay using a monoclonal antibody from the hybridoma cell line clone anti-DAO 8/119 provided by Prof. Quaroni (Cornell University, Ithaca, NY), and Amplex red™ was used. High-protein binding black fluorescence plates (475,515, Thermo Scientific Nunc, Denmark) were coated with 100 µl of 5 µg/ml anti-DAO 8/119 in 50 mM carbonate-bicarbonate buffer (C3041, Sigma-Aldrich, Austria), incubated overnight at 4 °C and subsequently blocked with 120 µl 1% BSA (A4503, Sigma-Aldrich, Austria) for 50 min at room temperature. After blocking 100 µl of plasma samples and standards, previously diluted 1:10 in PBS were added and incubated for 1 h at room temperature. Afterward 90 µl horseradish peroxidase (final concentration 1.2 µg/ml) and Amplex red™ (final concentration 100 µM) in PBS with 0.1% BSA were added and reactions were started by adding 10 µl putrescine (final concentration 200 µM) or PBS. Fluorescence was measured at 37 °C every 5 min for 120 min using EX550 and EM590 nm. The washing solution was 0.1% Tween-20 (P1379, Sigma-Aldrich, Austria) in PBS. A standard curve of 3–30 ng/ml rhDAO was prepared in mouse plasma. All measurements were performed in duplicate.

Histamine measurements

Citrate plasma containing 10 µM diminazene-aceturate (D7770, Sigma-Aldrich, Austria) was used to measure histamine concentrations using the histamine homogeneous time-resolved fluorescence (HTRF) dynamic kit (62HTMDPET, Cisbio, France). The kit was used according to the instructions provided by the manufacturer. A histamine standard curve in pooled plasma of C57Bl/6J mice was used for quantification. All histamine concentrations refer to the histamine base and all measurements were performed in duplicate.

Statistical analysis

Statistical analyses were performed using GraphPad Prism Version 8.4.0. (GraphPad Software Inc. San Diego). Statistical significance for differences in DAO activity in tissue homogenates was calculated using a repeated-measures ANOVA with Geisser–Greenhouse correction. The area under the curves (AUC) from individual core body temperature measurements and clinical scores during an experiment were compared using two-sided, unpaired t-tests without Welch’s correction. Plasma histamine concentrations between groups were compared with a two-way ANOVA. For comparison of plasma histamine concentrations after s.c. the challenge between mice with different genotypes, with and without acute kidney injury and receiving either DAO or buffer, data were grouped into intervals to account for missing values in individual subgroups (genotypes: 5, 10, 20, 30, 40, 45, 60 min; acute kidney injury: 0, 10–15, 20–30, 40–45 and 60 min; DAO: 0, 10, 30 and 45 min). A two-sided, unpaired t-test was used to test for differences in plasma creatinine concentrations from mice treated with and without 100 mg/kg folic acid. Statistical significance was defined as p<0.05 in all tests.

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Conclusion

DAO KO mice were essentially indistinguishable from WT mice using exogenous oral and subcu￾cutaneous histamine challenges. The involvement of HNMT in the inactivation of histamine leading to reduced symptoms￾topology is moderate at best but results from pharmacology￾cal inhibition might be considered preliminary. Data using inhibition of HNMT with methoprene showed a trend toward the involvement of endogenous DAO in histamine inactivation. The kidneys are involved in the rapid extraction of histamine from the circulation, but the sevenfold elevated 509 Diamine oxidase knockout mice are not hypersensitive to orally or subcutaneously administered… 1 3 histamine concentrations did not translate into an exaggerated phenotype measured using central temperature loss as phenotypical readout. The use of recombinant human or mouse DAO might support or help dismiss the involvement of histamine in various animal models with suspected mast cell degranulation accompanied by rapid and massive histamine release, or with enhanced induction of the histidine decarboxylase enzyme followed by the release of freshly synthesized histamine over hours. Breeding a true double KO mouse with inactive copies of both the DAO and the HNMT gene, if viable, might be worth studying. Single KO mice of either DAO or HNMT do not show obvious phenotypes. [unpublished data, 31] Similarly, testing the involvement of the two main histamine transporters, OCT2 and OCT3, in histamine-induced phenotypical alterations might allow us to gain a better understanding of the mechanisms behind the development of histamine-mediated symptoms in rodents and consequently potentially also in humans. Despite significant research efforts for more than 100 years since its discovery we still have some way to go before we gain a true understanding of histamine catabolism.

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Matthias Karer1 · Marlene Rager‑Resch1 · Teresa Haider2 · Karin Petroczi1 · Elisabeth Gludovacz3 · Nicole Borth3 · Bernd Jilma1 · Thomas Boehm1

1 Department of Clinical Pharmacology, Medical University Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria

2 Department of Neurophysiology, Center for Brain Research, Medical University Vienna, Vienna, Austria

3 Department of Biotechnology, University of Natural Resources and Life Sciences, Vienna, Austria