paraxanthine

Paraxanthine is not known to be produced by plants{{Cite journal|last=Stavric|first=B.|date=1988-01-01|title=Methylxanthines: Toxicity to humans. 3. Theobromine, paraxanthine and the combined effects of methylxanthines|journal=Food and Chemical Toxicology|language=en|volume=26|issue=8|pages=725–733|doi=10.1016/0278-6915(88)90073-7|pmid=3058562|issn=0278-6915}} but is observed in nature as a metabolite of caffeine in animals and some species of bacteria.{{cite journal | vauthors = Mazzafera P | title = Catabolism of caffeine in plants and microorganisms | journal = Frontiers in Bioscience | volume = 9 | issue = 1–3| pages = 1348–59 | date = May 2004 | pmid = 14977550 | doi = 10.2741/1339| doi-access = free }}

Paraxanthine is the primary metabolite of caffeine in humans and other animals, such as mice.{{cite journal | vauthors = Fuhr U, Doehmer J, Battula N, Wölfel C, Flick I, Kudla C, Keita Y, Staib AH | title = Biotransformation of methylxanthines in mammalian cell lines genetically engineered for expression of single cytochrome P450 isoforms. Allocation of metabolic pathways to isoforms and inhibitory effects of quinolones | journal = Toxicology | volume = 82 | issue = 1–3 | pages = 169–89 | date = October 1993 | pmid = 8236273 | doi = 10.1016/0300-483x(93)90064-y | bibcode = 1993Toxgy..82..169F }} Shortly after ingestion, roughly 84% of caffeine is metabolized into paraxanthine by hepatic cytochrome P450, which removes a methyl group from the N3 position of caffeine.{{cite journal | vauthors = Guerreiro S, Toulorge D, Hirsch E, Marien M, Sokoloff P, Michel PP | title = Paraxanthine, the primary metabolite of caffeine, provides protection against dopaminergic cell death via stimulation of ryanodine receptor channels | journal = Molecular Pharmacology | volume = 74 | issue = 4 | pages = 980–9 | date = October 2008 | pmid = 18621927 | doi = 10.1124/mol.108.048207 | s2cid = 14842240 }}{{cite journal | vauthors = Graham TE, Rush JW, van Soeren MH | title = Caffeine and exercise: metabolism and performance | journal = Canadian Journal of Applied Physiology | volume = 19 | issue = 2 | pages = 111–38 | date = June 1994 | pmid = 8081318 | doi = 10.1139/h94-010 }}{{cite journal | vauthors = Mazzafera P | title = Catabolism of caffeine in plants and microorganisms | journal = Frontiers in Bioscience | volume = 9 | issue = 1–3 | pages = 1348–59 | date = May 2004 | pmid = 14977550 | doi = 10.2741/1339 | doi-access = free }} After formation, paraxanthine can be broken down to 7-methylxanthine by demethylation of the N1 position,{{cite journal | vauthors = Summers RM, Mohanty SK, Gopishetty S, Subramanian M | title = Genetic characterization of caffeine degradation by bacteria and its potential applications | journal = Microbial Biotechnology | volume = 8 | issue = 3 | pages = 369–78 | date = May 2015 | pmid = 25678373 | pmc = 4408171 | doi = 10.1111/1751-7915.12262 }} which is subsequently demethylated into xanthine or oxidized by CYP2A6 and CYP1A2 into 1,7-dimethyluric acid. In another pathway, paraxanthine is broken down into 5-acetylamino-6-formylamino-3-methyluracil through N-acetyl-transferase 2, which is then broken down into 5-acetylamino-6-amino-3-methyluracil by non-enzymatic decomposition.{{Cite book |title=Caffeine : chemistry, analysis, function and effects|others=Preedy, Victor R.,, Royal Society of Chemistry (Great Britain)|isbn=9781849734752|location=Cambridge, U.K.|oclc=810337257|year=2012}} In yet another pathway, paraxanthine is metabolized CYPIA2 forming 1-methyl-xanthine, which can then be metabolized by xanthine oxidase to form 1-methyl-uric acid.

Certain proposed synthetic pathways of caffeine make use of paraxanthine as a bypass intermediate. However, its absence in plant alkaloid assays implies that these are infrequently, if ever, directly produced by plants.{{Citation needed|date=September 2008}}

{{more medical citations|section|date=November 2021}}

Like caffeine, paraxanthine is a psychoactive central nervous system (CNS) stimulant.

Studies indicate that, similar to caffeine, simultaneous antagonism of adenosine receptors{{cite journal|vauthors=Daly JW, Jacobson KA, Ukena D|year=1987|title=Adenosine receptors: development of selective agonists and antagonists|journal=Progress in Clinical and Biological Research|volume=230|issue=1|pages=41–63|pmid=3588607}} is responsible for paraxanthine's stimulatory effects. Paraxanthine adenosine receptor binding affinity (21 μM for A1, 32 μM for A2_A, 4.5 μM for A2_B, and >100 for μM for A3) is similar or slightly stronger than caffeine, but weaker than theophylline.{{Citation|last1=Müller|first1=Christa E.|title=Xanthines as Adenosine Receptor Antagonists|date=2011|work=Methylxanthines|pages=151–199|editor-last=Fredholm|editor-first=Bertil B.|series=Handbook of Experimental Pharmacology|publisher=Springer|language=en|doi=10.1007/978-3-642-13443-2_6|isbn=978-3-642-13443-2|pmc=3882893|pmid=20859796|last2=Jacobson|first2=Kenneth A.|volume=200 |issue=200}}

Paraxanthine is a selective inhibitor of cGMP-preferring phosphodiesterase (PDE9) activity{{Cite journal|last1=Orrú|first1=Marco|last2=Guitart|first2=Xavier|last3=Karcz-Kubicha|first3=Marzena|last4=Solinas|first4=Marcello|last5=Justinova|first5=Zuzana|last6=Barodia|first6=Sandeep Kumar|last7=Zanoveli|first7=Janaina|last8=Cortes|first8=Antoni|last9=Lluis|first9=Carme|last10=Casado|first10=Vicent|last11=Moeller|first11=F. Gerard|date=April 2013|title=Psychostimulant pharmacological profile of paraxanthine, the main metabolite of caffeine in humans|journal=Neuropharmacology|volume=67C|pages=476–484|doi=10.1016/j.neuropharm.2012.11.029|issn=0028-3908|pmc=3562388|pmid=23261866}} and is hypothesized to increase glutamate and dopamine release by potentiating nitric oxide signaling.{{Cite journal|last1=Ferré|first1=Sergi|last2=Orrú|first2=Marco|last3=Guitart|first3=Xavier|date=2013|title=Paraxanthine: Connecting Caffeine to Nitric Oxide Neurotransmission|journal=Journal of Caffeine Research|volume=3|issue=2|pages=72–78|doi=10.1089/jcr.2013.0006|issn=2156-5783|pmc=3680978|pmid=24761277}} Activation of a nitric oxide-cGMP pathway may be responsible for some of the behavioral effects of paraxanthine that differ from those associated with caffeine.{{Cite journal|last=Orrú|first=Marco|date=2013|title=Psychostimulant pharmacological profile of paraxanthine, the main metabolite of caffeine in humans|journal=Neuropharmacology|volume=67C|pages=476–484|pmc=3562388|pmid=23261866|doi=10.1016/j.neuropharm.2012.11.029}}

Paraxanthine is a competitive nonselective phosphodiesterase inhibitor{{cite journal | vauthors = Essayan DM | title = Cyclic nucleotide phosphodiesterases | journal = The Journal of Allergy and Clinical Immunology | volume = 108 | issue = 5 | pages = 671–80 | date = November 2001 | pmid = 11692087 | doi = 10.1067/mai.2001.119555 | doi-access = free }} which raises intracellular cAMP, activates PKA, inhibits TNF-alpha{{cite journal | vauthors = Deree J, Martins JO, Melbostad H, Loomis WH, Coimbra R | title = Insights into the regulation of TNF-alpha production in human mononuclear cells: the effects of non-specific phosphodiesterase inhibition | journal = Clinics | volume = 63 | issue = 3 | pages = 321–8 | date = June 2008 | pmid = 18568240 | pmc = 2664230 | doi = 10.1590/S1807-59322008000300006 }}{{cite journal | vauthors = Marques LJ, Zheng L, Poulakis N, Guzman J, Costabel U | title = Pentoxifylline inhibits TNF-alpha production from human alveolar macrophages | journal = American Journal of Respiratory and Critical Care Medicine | volume = 159 | issue = 2 | pages = 508–11 | date = February 1999 | pmid = 9927365 | doi = 10.1164/ajrccm.159.2.9804085 }} and leukotriene{{cite journal | vauthors = Peters-Golden M, Canetti C, Mancuso P, Coffey MJ | title = Leukotrienes: underappreciated mediators of innate immune responses | journal = Journal of Immunology | volume = 174 | issue = 2 | pages = 589–94 | date = January 2005 | pmid = 15634873 | doi = 10.4049/jimmunol.174.2.589 | url = http://www.jimmunol.org/cgi/content/full/174/2/589 | doi-access = free }} synthesis, and reduces inflammation and innate immunity.

Unlike caffeine, paraxanthine acts as an enzymatic effector of Na⁺/K⁺ ATPase. As a result, it is responsible for increased transport of potassium ions into skeletal muscle tissue.{{cite journal | vauthors = Hawke TJ, Willmets RG, Lindinger MI | title = K+ transport in resting rat hind-limb skeletal muscle in response to paraxanthine, a caffeine metabolite | journal = Canadian Journal of Physiology and Pharmacology | volume = 77 | issue = 11 | pages = 835–43 | date = November 1999 | pmid = 10593655 | doi = 10.1139/y99-095 }} Similarly, the compound also stimulates increases in calcium ion concentration in muscle.{{cite journal | vauthors = Hawke TJ, Allen DG, Lindinger MI | title = Paraxanthine, a caffeine metabolite, dose dependently increases [Ca(2+)](i) in skeletal muscle | journal = Journal of Applied Physiology | volume = 89 | issue = 6 | pages = 2312–7 | date = December 2000 | pmid = 11090584 | doi = 10.1152/jappl.2000.89.6.2312 | s2cid = 11369121 | doi-access = free }}

The pharmacokinetic parameter for paraxanthine are similar to those for caffeine, but differ significantly from those for theobromine and theophylline, the other major caffeine-derived methylxanthine metabolites in humans.

Paraxanthine is a phosphodiesterase type 9 (PDE9) inhibitor and it is sold as a research molecule for this same purpose.{{Cite web|url=https://www.caymanchem.com/pdfs/21068.pdf|title=Paraxanthine}}

Paraxanthine is believed to exhibit a lower toxicity than caffeine and the caffeine metabolite, theophylline.{{cite journal|journal=Clinical Pharmacology & Therapeutics|year=1995|issue=6|pages=684–691|title=Sympathomimetic effects of paraxanthine and caffeine in humans |author1 =Neal L. Benowitz |author2 =Peyton Jacob |author3 =Haim Mayan |author4 =Charles Denaro |url=http://www.nature.com/clpt/journal/v58/n6/abs/clpt1995184a.html| doi= 10.1016/0009-9236(95)90025-X|pmid=8529334|volume=58|s2cid=22747642|url-access=subscription}}{{Cite book|last=Institute of Medicine (US) Committee on Military Nutrition Research|url=http://www.ncbi.nlm.nih.gov/books/NBK223802/|title=Caffeine for the Sustainment of Mental Task Performance: Formulations for Military Operations|date=2001|publisher=National Academies Press (US)|isbn=978-0-309-08258-7|location=Washington (DC)|pmid=25057583}} In a mouse model, intraperitoneal paraxanthine doses of 175 mg/kg/day did not result in animal death or overt signs of stress;{{Cite journal|last1=York|first1=R. G.|last2=Randall|first2=J. L.|last3=Scott|first3=W. J.|date=1986|title=Teratogenicity of paraxanthine (1,7-dimethylxanthine) in C57BL/6J mice|journal=Teratology|volume=34|issue=3|pages=279–282|doi=10.1002/tera.1420340307|issn=0040-3709|pmid=3798364}} by comparison, the intraperitoneal _LD50 for caffeine in mice is reported at 168 mg/kg.{{Cite book|url=https://books.google.com/books?id=fDVaIb9H7DAC&q=caffeine+mouse+LD50+intraperitoneal+168+mg%2Fkg&pg=PA1373|title=Registry of Toxic Effects of Chemical Substances|date=1987|publisher=National Institute for Occupational Safety and Health|language=en}} In in vitro cell culture studies, paraxanthine is reported to be less harmful than caffeine and the least harmful of the caffeine-derived metabolites in terms of hepatocyte toxicity.{{Cite journal|last1=Gressner|first1=Olav A.|last2=Lahme|first2=Birgit|last3=Siluschek|first3=Monika|last4=Gressner|first4=Axel M.|date=2009|title=Identification of paraxanthine as the most potent caffeine-derived inhibitor of connective tissue growth factor expression in liver parenchymal cells|journal=Liver International|volume=29|issue=6|pages=886–897|doi=10.1111/j.1478-3231.2009.01987.x|issn=1478-3231|pmid=19291178|s2cid=32926935}}

As with other methylxanthines, paraxanthine is reported to be teratogenic when administered in high doses; but it is a less potent teratogen as compared to caffeine and theophylline. A mouse study on the potentiating effects of methylxanthines coadministered with mitomycin C on teratogenicity reported the incidence of birth defects for caffeine, theophylline, and paraxanthine to be 94.2%, 80.0%, and 16.9%, respectively; additionally, average birth weight decreased significantly in mice exposed to caffeine or theophylline when coadministered with mitomycin C, but not for paraxanthine coadministered with mitomycin C.{{Cite journal|last1=Nakatsuka|first1=Toshio|last2=Hanada|first2=Satoshi|last3=Fujii|first3=Takaaki|date=1983|title=Potentiating effects of methylxanthines on teratogenicity of mitomycin C in mice|journal=Teratology|language=en|volume=28|issue=2|pages=243–247|doi=10.1002/tera.1420280214|pmid=6417813|issn=1096-9926}}

Paraxanthine was reported to be significantly less clastogenic compared to caffeine or theophylline in an in vitro study using human lymphocytes.{{Cite journal|last1=Weinstein|first1=David|last2=Mauer|first2=Irving|last3=Katz|first3=Marion L.|last4=Kazmer|first4=Sonja|date=1975|title=The effect of methylxanthines on chromosomes of human lymphocytes in culture|journal=Mutation Research/Environmental Mutagenesis and Related Subjects|language=en|volume=31|issue=1|pages=57–61|doi=10.1016/0165-1161(75)90064-3|pmid=1128545|issn=0165-1161}}

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Category:Adenosine receptor antagonists

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Category:Stimulants

Category:Wakefulness-promoting agents

Category:Xanthines