Pharmacokinetics and Metabolism of Natural Methylxanthines in Animal and Man

Arnaud, Maurice J.

doi:10.1007/978-3-642-13443-2_3

Cited by 209 publications

(263 citation statements)

References 250 publications

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“…Caffeine easily cross barriers in the body and is eliminated with half time up to 10 hours (28). Beside the elimination, it is metabolized by CYP1A2 (29,30). Here reported result on the improvement of oxidative balance in the brain is in a good compliance with data known in literature where caffeine is reported as a protective factor of neuronal cells (31).…”

Section: Discussionsupporting

confidence: 85%

Caffeine alters oxidative homeostasis in the body of BALB/c mice

Pohanka¹

2014

BLL

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Caffeine is a metabolite from coffee genus and some other plants. It has disparate molecular targets in the body. Beside the major action based on antagonism on adenosine receptor, it is involved in other neurotransmission pathways as well. The complete mechanism of caffeine action remains unrevealed including link to oxidative homeostasis. For the reason, the current paper solves how caffeine infl uences oxidative homeostasis in BALB/c mouse model. Caffeine was given intramuscularly in doses 1-64 mg/kg and the animals were sacrifi ced in time intervals from 4 hours up to 3 days. In the experiment, a signifi cant increase of thiobarbituric acid reactive substances (TBARS) levels in the kidney and decrease in the brain indicated up and down regulation of oxidative burden. Ferric reducing antioxidant power (FRAP) level in the kidney appoint at release of low molecular weight antioxidants in the organ. The remaining organs including heart, muscles and liver were intact. In the same way, caspase 3 level was steady and no apoptotic processes were proved (Fig. 3

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Section: Discussionsupporting

confidence: 85%

Caffeine alters oxidative homeostasis in the body of BALB/c mice

Pohanka¹

2014

BLL

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“…Humans metabolize caffeine mainly via N-demethylation catalyzed by the hepatic cytochrome P450s 1A2 and 2E1 (2). Various bacteria have been reported to metabolize caffeine and related methylxanthines by N-demethylation.…”

mentioning

confidence: 99%

Novel, Highly Specific N -Demethylases Enable Bacteria To Live on Caffeine and Related Purine Alkaloids

et al. 2012

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cThe molecular basis for the ability of bacteria to live on caffeine as a sole carbon and nitrogen source is unknown. Pseudomonas putida CBB5, which grows on several purine alkaloids, metabolizes caffeine and related methylxanthines via sequential N-demethylation to xanthine. Metabolism of caffeine by CBB5 was previously attributed to one broad-specificity methylxanthine Ndemethylase composed of two subunits, NdmA and NdmB. Here, we report that NdmA and NdmB are actually two independent Rieske nonheme iron monooxygenases with N 1 -and N 3 -specific N-demethylation activity, respectively. Activity for both enzymes is dependent on electron transfer from NADH via a redox-center-dense Rieske reductase, NdmD. NdmD itself is a novel protein with one Rieske [2Fe-2S] cluster, one plant-type [2Fe-2S] cluster, and one flavin mononucleotide (FMN) per enzyme. All ndm genes are located in a 13.2-kb genomic DNA fragment which also contained a formaldehyde dehydrogenase. ndmA, ndmB, and ndmD were cloned as His 6 fusion genes, expressed in Escherichia coli, and purified using a Ni-NTA column. NdmA-His 6 plus His 6 -NdmD catalyzed N 1 -demethylation of caffeine, theophylline, paraxanthine, and 1-methylxanthine to theobromine, 3-methylxanthine, 7-methylxanthine, and xanthine, respectively. NdmB-His 6 plus His 6 -NdmD catalyzed N 3 -demethylation of theobromine, 3-methylxanthine, caffeine, and theophylline to 7-methylxanthine, xanthine, paraxanthine, and 1-methylxanthine, respectively. One formaldehyde was produced from each methyl group removed. Activity of an N 7 -specific N-demethylase, NdmC, has been confirmed biochemically. This is the first report of bacterial N-demethylase genes that enable bacteria to live on caffeine. These genes represent a new class of Rieske oxygenases and have the potential to produce biofuels, animal feed, and pharmaceuticals from coffee and tea waste. Many natural products and xenobiotic compounds contain N-linked methyl groups. A search of the Combined Chemical Dictionary database (http://ccd.chemnetbase.com) identified 19,091 compounds out of approximately 500,000 entries that contain at least one N-methyl group. N-Demethylations of many of these compounds by members of cytochrome P450, flavoenzyme, and 2-ketoglutarate-dependent nonheme iron oxygenase families are critical biological processes in living organisms (1,12,17,27,31). These processes include detoxification of drugs and xenobiotic compounds, regulation of chromatin dynamics and gene transcription, and repair of alkylation damages in purine and pyrimidine bases in nucleic acids. Members of all aforementioned enzyme families also catalyze O-demethylation reactions (14). Bacteria have evolved highly specific Rieske [2Fe-2S] domaincontaining O-demethylases that belong to the Rieske oxygenase (RO) family for the degradation of methoxybenzoates (5, 16). However, to the best of our knowledge, there is no description of N-demethylation by ROs.Caffeine (1,3,7-trimethylxanthine) and related N-methylated xanthines are purine alkaloids that are ext...

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“…34,35 In humans, caffeine is also rapidly metabolized to the three dimethylxanthines, but with a very different metabolizing rate, with paraxanthine constituting by far the main metabolite (approximately 80% of the three dimethylxanthines). [34][35][36] The first studies which compared the pharmacological effects of caffeine and its main metabolites were FIG. 1.…”

Section: Different Pharmacological Profile Of Paraxanthine Compared Tmentioning

confidence: 99%

Paraxanthine: Connecting Caffeine to Nitric Oxide Neurotransmission

Ferré

Orrù

Guitart

2013

Journal of Caffeine Research

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Recent results obtained in our laboratory indicate that paraxanthine, the main metabolite of caffeine in humans, produces a significantly stronger locomotor activation in rats than caffeine. Furthermore, paraxanthine also produced a very significant increase in striatal extracellular concentrations of dopamine. Searching for an additional mechanism other than adenosine antagonism responsible for these psychostimulant-like effects, it was found that paraxanthine, but not caffeine, inhibited cGMP-preferring phosphodiesterases. Furthermore, interrupting nitric oxide neurotransmision (inhibiting nitric oxide synthase) significantly decreased both the locomotor-activating and the dopamine-releasing effects of paraxanthine. These results open up some obvious questions about the role of paraxanthine in the pharmacological effects of caffeine. Nitric Oxide Neurotransmission S ince nitric oxide (NO) was first identified as an endothelial-derived relaxation factor in peripheral blood vessels, 1 its role as a biological messenger, and particularly as a neurotransmitter has been well established. Thus, NO fits within the broad definition of neurotransmitter coined by Snyder and Ferris 2-that is, ''a molecule, released by neu-rons or glia, which physiologically influences the electro-chemical state of adjacent cells''. Because NO cannot be stored in cells, it depends on new synthesis to exert its functional properties. NO is produced by NO synthase (NOS), which generates NO from the amino acid L-arginine. NOS is a complex heterodimeric protein that is found constitu-tively in two isoforms, neuronal, and endothelial NO (nNOS and eNOS, respectively). A third inducible form (iNOS) can be expressed by macrophages and microglia upon immunological challenge. 3 nNOS is the most abundant isoform found in the brain and the one responsible for NO production in neurons and its enzyme activity is regulated by Ca 2+ and calmodulin. 4 The subcellular localization of nNOS is mediated by its ability to bind to adapter proteins. For instance, through its PDZ domain it binds to PSD95 (post-synaptic density protein 95), which links nNOS to the N-methyl-D-aspartate (NMDA) receptor and accounts for the efficient activation of nNOS by NMDA receptor stimulation. 5 In the central nervous system, nNOS is synthesized by specific populations of neurons (NO neurons). In the cerebellum, nNOS is expressed by local stellate, basket and granule, but not Purkinje cells, although Purkinje are abundant in NO receptors. 6 In the brainstem, nNOS is produced by cholinergic neurons of the ascending reticular activating system. 6 These cells originate in the latero-dorsal and pedunculo-pontine nu-clei (LDT and PPT nuclei), which through a dorsal tegmental pathway project heavily to the thalamus, to the midline-intralaminar and reticular nuclei, which transmit the activity of the ascending reticular activating system to extensive areas of the cerebral cortex (for a recent review see ref. 7). Through a ventral tegmental pathway the cholinergic cells of the LDT and P...

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Pharmacokinetics and Metabolism of Natural Methylxanthines in Animal and Man

Cited by 209 publications

References 250 publications

Caffeine alters oxidative homeostasis in the body of BALB/c mice

Caffeine alters oxidative homeostasis in the body of BALB/c mice

Novel, Highly Specific N -Demethylases Enable Bacteria To Live on Caffeine and Related Purine Alkaloids

Paraxanthine: Connecting Caffeine to Nitric Oxide Neurotransmission

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