Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Paraxanthine: Difference between pages

| Watchedfields = changed

| verifiedrevid = 464197387

| Name = Paraxanthine

| ImageFile = Paraxanthine structure.svg

| ImageSize = 150

| ImageName = Skeletal formula of paraxanthine

| ImageFile1 = Paraxanthine 3D ball.png

| ImageSize1 = 180

| ImageAlt1 = Ball-and-stick model of the paraxanthine model

| IUPACName = 1,7-Dimethyl-3''H''-purine-2,6-dione

| OtherNames = Paraxanthine, <br /> 1,7-Dimethylxanthine

| UNII_Ref = {{fdacite|correct|FDA}}

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| CASNo = 611-59-6

| C=7|H=8|N=4|O=2

| MeltingPtC = 351 to 352

}}

'''Paraxanthine''', also known as 1,7-dimethylxanthine, is a metabolite of [[theophylline]] and [[theobromine]], two well-known stimulants found in coffee, tea, and chocolate mainly in the form of caffeine. It is a member of the [[xanthine]] family of [[alkaloids]], which includes theophylline, theobromine and [[caffeine]].

==Production and metabolism==

Paraxanthine is not known to be produced by plants<ref>{{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}}</ref> but is observed in nature as a [[metabolite]] of [[caffeine]] in animals and some species of bacteria.<ref name="Mazzafera_2004">{{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 }}</ref>

Paraxanthine is the primary metabolite of caffeine in humans and other animals, such as mice.<ref>{{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 }}</ref> Shortly after ingestion, roughly 84% of caffeine is metabolized into paraxanthine by [[Cytochrome P450|hepatic cytochrome P450]], which removes a methyl group from the N3 position of caffeine.<ref name="pmid18621927">{{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 }}</ref><ref>{{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 }}</ref><ref name=":2">{{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 }}</ref> After formation, paraxanthine can be broken down to [[7-methylxanthine]] by demethylation of the N1 position,<ref>{{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 }}</ref> which is subsequently demethylated into xanthine or oxidized by CYP2A6 and CYP1A2 into 1,7-dimethyluric acid.<ref name=":2" /> 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.<ref name=":0">{{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}}</ref> 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.<ref name=":0" />

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}}

==Pharmacology and physiological effects==

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

Like caffeine, paraxanthine is a [[psychoactive]] [[central nervous system]] (CNS) [[stimulant]].<ref name="Mazzafera_2004" />

===Pharmacodynamics===

Studies indicate that, similar to caffeine, simultaneous antagonism of [[adenosine receptor]]s<ref name="AR-Daly">{{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}}</ref> is responsible for paraxanthine's stimulatory effects. Paraxanthine adenosine receptor binding affinity (21 μM for [[Adenosine A1 receptor|A1]], 32 μM for [[Adenosine A2A receptor|A2_A]], 4.5 μM for [[Adenosine A2B receptor|A2_B]], and >100 for μM for [[Adenosine A3 receptor|A3]]) is similar or slightly stronger than caffeine, but weaker than theophylline.<ref>{{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}}</ref>

Paraxanthine is a selective inhibitor of cGMP-preferring [[phosphodiesterase]] (PDE9) activity<ref>{{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}}</ref> and is hypothesized to increase glutamate and [[dopamine]] release by potentiating nitric oxide signaling.<ref>{{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}}</ref> Activation of a nitric oxide-[[Cyclic guanosine monophosphate|cGMP]] pathway may be responsible for some of the behavioral effects of paraxanthine that differ from those associated with caffeine.<ref name=":1">{{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}}</ref>

Paraxanthine is a competitive nonselective [[phosphodiesterase inhibitor]]<ref name="PDEs-Essayan">{{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 }}</ref> which raises intracellular [[Cyclic adenosine monophosphate|cAMP]], activates [[cAMP-dependent protein kinase|PKA]], [[TNF inhibitor|inhibits TNF-alpha]]<ref name="PTX-Deree">{{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 }}</ref><ref name="pmid9927365">{{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 }}</ref> and [[leukotriene]]<ref name="LT-Peters-Golden">{{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 }}</ref> synthesis, and [[Anti-inflammatory|reduces inflammation]] and [[innate immunity]].<ref name="LT-Peters-Golden" />

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.<ref name="pmid10593655">{{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 }}</ref> Similarly, the compound also stimulates increases in [[calcium]] ion concentration in muscle.<ref name="pmid11090584">{{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 }}</ref>

===Pharmacokinetics===

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 (Table 1).

{| class="wikitable"

|+Table 1. Comparative pharmacokinetics of caffeine, and caffeine-derived methylxanthines<ref>{{Cite journal|last1=Lelo|first1=A.|last2=Birkett|first2=D. J.|last3=Robson|first3=R. A.|last4=Miners|first4=J. O.|date=August 1986|title=Comparative pharmacokinetics of caffeine and its primary demethylated metabolites paraxanthine, theobromine and theophylline in man|journal=British Journal of Clinical Pharmacology|volume=22|issue=2|pages=177–182|doi=10.1111/j.1365-2125.1986.tb05246.x|issn=0306-5251|pmc=1401099|pmid=3756065}}</ref>

!

![[Biological half-life|Plasma Half-Life]]

(t_1/2; hr)

!Volume of Distribution

(V_ss,unbound; l/kg)

!Plasma Clearance

(CL; ml/min/kg)

|-

|[[Caffeine]]

|4.1 ± 1.3

|1.06 ± 0.26

|2.07 ± 0.96

|-

|Paraxanthine

|3.1 ± 0.8

|1.18 ± 0.37

|2.20 ± 0.91

|-

|[[Theobromine]]

|7.2 ± 1.6

|0.79 ± 0.15

|1.20 ± 0.40

|-

|[[Theophylline]]

|6.2 ± 1.4

|0.77 ± 0.17

|0.93 ± 0.22

|}

===Uses===

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

== Toxicity ==

Paraxanthine is believed to exhibit a lower [[toxicity]] than caffeine and the caffeine metabolite, [[theophylline]].<ref>{{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}}</ref><ref>{{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}}</ref> In a mouse model, intraperitoneal paraxanthine doses of 175&nbsp;mg/kg/day did not result in animal death or overt signs of stress;<ref name=":3">{{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}}</ref> by comparison, the intraperitoneal [[Median lethal dose|LD50]] for caffeine in mice is reported at 168&nbsp;mg/kg.<ref>{{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}}</ref> 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.<ref>{{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}}</ref>

As with other methylxanthines, paraxanthine is reported to be [[teratogenic]] when administered in high doses;<ref name=":3" /> 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.<ref>{{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}}</ref>

Paraxanthine was reported to be significantly less [[clastogen]]ic compared to caffeine or theophylline in an ''in vitro'' study using human lymphocytes.<ref>{{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}}</ref>

== References ==

{{Reflist|2}}

== External links ==

*{{Commons category-inline}}

{{Stimulants}}

{{Adenosinergics}}

{{Phosphodiesterase inhibitors}}

[[Category:Adenosine receptor antagonists]]

[[Category:Animal metabolites]]

[[Category:Phosphodiesterase inhibitors]]

[[Category:Stimulants]]

[[Category:Xanthines]]

[[Category:Human drug metabolites]]