Theobromine and related methylxanthines as inhibitors of Primary Amine Oxidase

Shanahan, Padraig; O'Sullivan, Jeff; Tipton, Keith F.; Kinsella, Gemma K.; Ryan, Barry J.; Henehan, Gary

doi:10.1111/jfbc.12697

Cited by 11 publications

(29 citation statements)

References 32 publications

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“…There are also anti-inflammatory actions attributed to methylxanthines [8,9] although the mode of action remains more elusive than for their psychostimulant or dilator activities [8,10,11]. The recent demonstration of an inhibitory effect of methylxanthines on bovine amine oxidase [12] is in agreement with such anti-inflammatory actions. Bovine plasma amine oxidase is a copper-containing amine oxidase, an ortholog to the product of the human AOC3 gene (Amine Oxidase, Copper-Containing 3) [13,14].…”

Section: Introductionmentioning

confidence: 74%

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Methylxanthines Inhibit Primary Amine Oxidase and Monoamine Oxidase Activities of Human Adipose Tissue

et al. 2020

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Background: Methylxanthines including caffeine and theobromine are widely consumed compounds and were recently shown to interact with bovine copper-containing amine oxidase. To the best of our knowledge, no direct demonstration of any interplay between these phytochemicals and human primary amine oxidase (PrAO) has been reported to date. We took advantage of the coexistence of PrAO and monoamine oxidase (MAO) activities in human subcutaneous adipose tissue (hScAT) to test the interaction between several methylxanthines and these enzymes, which are involved in many key pathophysiological processes. Methods: Benzylamine, methylamine, and tyramine were used as substrates for PrAO and MAO in homogenates of subcutaneous adipose depots obtained from overweight women undergoing plastic surgery. Methylxanthines were tested as substrates or inhibitors by fluorimetric determination of hydrogen peroxide, an end-product of amine oxidation. Results: Semicarbazide-sensitive PrAO activity was inhibited by theobromine, caffeine, and isobutylmethylxanthine (IBMX) while theophylline, paraxanthine, and 7-methylxanthine had little effect. Theobromine inhibited PrAO activity by 54% at 2.5 mM. Overall, the relationship between methylxanthine structure and the degree of inhibition was similar to that seen with bovine PrAO, although higher concentrations (mM) were required for inhibition. Theobromine also inhibited oxidation of tyramine by MAO, at the limits of its solubility in a DMSO vehicle. At doses higher than 12 % v/v, DMSO impaired MAO activity. MAO was also inhibited by millimolar doses of IBMX, caffeine and by other methylxanthines to a lesser extent. Conclusions: This preclinical study extrapolates previous findings with bovine PrAO to human tissues. Given that PrAO is a potential target for anti-inflammatory drugs, it indicates that alongside phosphodiesterase inhibition and adenosine receptor antagonism, PrAO and MAO inhibition could contribute to the health benefits of methylxanthines, especially their anti-inflammatory effects.

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Section: Introductionmentioning

confidence: 74%

“…The hypothesis that natural methylxanthines can inhibit human SSAO/VAP-1 has been proposed [12], but not yet verified. Such inhibition might contribute to the anti-inflammatory effect of methylxanthines.…”

Section: Introductionmentioning

confidence: 99%

Methylxanthines Inhibit Primary Amine Oxidase and Monoamine Oxidase Activities of Human Adipose Tissue

et al. 2020

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“…3-Methylxanthine and xanthine were common downstream metabolites detected in A. ustus and A. tamarii cultures. 3-Methylxanthine and other xanthine derivatives have been shown various biomedical effects as adenosine antagonist and inhibitors of Primary Amine Oxidase [57,58]. Besides chemical synthesis, biotransformation and biosynthesis offered alternative way to produce 3-methylxanthine and other xanthine derivatives [22,48].…”

Section: Discussionmentioning

confidence: 99%

Isolation, characterization and application of theophylline-degrading Aspergillus fungi

Zhou

Xia

et al. 2020

Microb Cell Fact

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Background: Caffeine, theobromine and theophylline are main purine alkaloid in tea. Theophylline is the downstream metabolite and it remains at a very low level in Camellia sinensis. In our previous study, Aspergillus sydowii could convert caffeine into theophylline in solid-state fermentation of pu-erh tea through N-demethylation. In this study, tea-derived fungi caused theophylline degradation in the solid-state fermentation. The purpose of this study is identify and isolate theophylline-degrading fungi and investigate their application in production of methylxanthines with theophylline as feedstock through microbial conversion.Results: Seven tea-derived fungi were collected and identified by ITS, β-tubulin and calmodulin gene sequences, Aspergillus ustus, Aspergillus tamarii, Aspergillus niger and A. sydowii associated with solid-state fermentation of pu-erh tea have shown ability to degrade theophylline in liquid culture. Particularly, A. ustus and A. tamarii could degrade theophylline highly significantly (p < 0.01). 1,3-dimethyluric acid, 3-methylxanthine, 3-methyluric acid, xanthine and uric acid were detected consecutively by HPLC in A. ustus and A. tamarii, respectively. The data from absolute quantification analysis suggested that 3-methylxanthine and xanthine were the main degraded metabolites in A. ustus and A. tamarii, respectively. 129.48 ± 5.81 mg/L of 3-methylxanthine and 159.11 ± 10.8 mg/L of xanthine were produced by A. ustus and A. tamarii in 300 mg/L of theophylline liquid medium, respectively. Conclusions:For the first time, we confirmed that isolated A. ustus, A. tamarii degrade theophylline through N-demethylation and oxidation. We were able to biologically produce 3-methylxanthine and xanthine efficiently from theophylline through a new microbial synthesis platform with A. ustus and A. tamarii as appropriate starter strains.

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“…Production of 3-methylxanthine through theobromine biodegradation 3-Methylxanthine and other methylxanthines have been shown various biomedical effects as adenosine receptors and inhibitors of Primary Amine Oxidase [39,40]. Due to high accumulation of 3-methylxanthine, 3-methylxanthine concentrations were determined by HPLC in sydowii PT-2 and A. tamarii PT-7 culture, respectively.…”

Section: Thebromine Degradation Characterization In Liquid Culturementioning

confidence: 99%

“…Until now, a bacterial strain Pseudomonas putida isolated from tea garden soil was demonstrated to degrade theobromine [26]. Additionally, A. niger, Talaromyces marneffei and Talaromyces verruculosus isolated from cocoa pod husks were demonstrated to degrade theobromine [39]. In this work, seven tea-derived fungal strains isolated from Pu-erh tea were used to investigate their capacity and characterization in theobromine degradation.…”

Section: Introductionmentioning

confidence: 99%

3-Methylxanthine production through biodegradation of theobromine by Aspergillus sydowii PT-2

Zhou

Zheng

et al. 2020

Preprint

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Abstract Background: Methylxanthines, including caffeine, theobromine and theophylline, are natural and synthetic compounds in tea, which could be metabolized by certain kinds of bacteria and fungi. Previous studies confirmed that several microbial isolates from Pu-erh tea could degrade and convert caffeine and theophylline. We speculated that these candidate isolates also could degrade and convert theobromine through N-demethylation and oxidation. In this study, seven tea-derived fungal strains were inoculated into various theobromine agar medias and theobromine liquid mediums to assess their capacity in theobromine utilization. Related metabolites with theobromine degradation were detected by using HPLC in the liquid culture to investigate their potential application in the production of 3-methylxanthine. Results: Based on theobromine utilization capacity, Aspergillus niger PT-1, Aspergillus sydowii PT-2, Aspergillus ustus PT-6 and Aspergillus tamarii PT-7 have demonstrated the potential for theobromine biodegradation. Particularly, A. sydowii PT-2 and A. tamarii PT-7 could degrade theobromine significantly (p < 0.05) in all given liquid mediums. 3,7-Dimethyluric acid, 3-methylxanthine, 7-methylxanthine, 3-methyluric acid, xanthine, and uric acid were detected in A. sydowii PT-2 and A. tamarii PT-7 culture, respectively, which confirmed the existence of N-demethylation and oxidation in theobromine catabolism. 3-Methylxanthine was common and main demethylated metabolite of theobromine in the liquid culture. 3-Methylxanthine in A. sydowii PT-2 culture showed a linear relation with initial theobromine concentrations that 177.12 ± 14.06 mg/L 3-methylxanthine was accumulated in TLM-S with 300 mg/L theobromine. Additionally, pH at 5 and metal ion of Fe2+ promoted 3-methylxanthine production significantly (p < 0.05). Conclusions: This study is the first to confirm that A. sydowii PT-2 and A. tamarii PT-7 degrade theobromine through N-demethylation and oxidation, respectively. A. sydowii PT-2 showed the potential application in 3-methylxanthine production with theobromine as feedstock through the N-demethylation at N-7 position.

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Theobromine and related methylxanthines as inhibitors of Primary Amine Oxidase

Cited by 11 publications

References 32 publications

Methylxanthines Inhibit Primary Amine Oxidase and Monoamine Oxidase Activities of Human Adipose Tissue

Methylxanthines Inhibit Primary Amine Oxidase and Monoamine Oxidase Activities of Human Adipose Tissue

Isolation, characterization and application of theophylline-degrading Aspergillus fungi

3-Methylxanthine production through biodegradation of theobromine by Aspergillus sydowii PT-2

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