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Paraxanthine

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Paraxanthine
Skeletal formula of paraxanthine
Ball-and-stick model of the paraxanthine model
Names
IUPAC name
1,7-Dimethyl-3H-purine-2,6-dione
Other names
Paraxanthine,
1,7-Dimethylxanthine
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.009.339 Edit this at Wikidata
UNII
  • InChI=1S/C7H8N4O2/c1-10-3-8-5-4(10)6(12)11(2)7(13)9-5/h3H,1-2H3,(H,9,13) checkY
    Key: QUNWUDVFRNGTCO-UHFFFAOYSA-N checkY
  • InChI=1/C7H8N4O2/c1-10-3-8-5-4(10)6(12)11(2)7(13)9-5/h3H,1-2H3,(H,9,13)
    Key: QUNWUDVFRNGTCO-UHFFFAOYAS
  • O=C2Nc1ncn(c1C(=O)N2C)C
Properties
C7H8N4O2
Molar mass 180.167 g·mol−1
Melting point 351 to 352 °C (664 to 666 °F; 624 to 625 K)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒N verify (what is checkY☒N ?)

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

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Paraxanthine is not known to be produced by plants[1] but is observed in nature as a metabolite of caffeine in animals and some species of bacteria.[2]

Paraxanthine is the primary metabolite of caffeine in humans and other animals, such as mice.[3] 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.[4][5][6] After formation, paraxanthine can be broken down to 7-methylxanthine by demethylation of the N1 position,[7] which is subsequently demethylated into xanthine or oxidized by CYP2A6 and CYP1A2 into 1,7-dimethyluric acid.[6] 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.[8] 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.[8]

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]

Pharmacology and physiological effects

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Like caffeine, paraxanthine is a psychoactive central nervous system (CNS) stimulant.[2]

Pharmacodynamics

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Studies indicate that, similar to caffeine, simultaneous antagonism of adenosine receptors[9] is responsible for paraxanthine's stimulatory effects. Paraxanthine adenosine receptor binding affinity (21 μM for A1, 32 μM for A2A, 4.5 μM for A2B, and >100 for μM for A3) is similar or slightly stronger than caffeine, but weaker than theophylline.[10]

Paraxanthine is a selective inhibitor of cGMP-preferring phosphodiesterase (PDE9) activity[11] and is hypothesized to increase glutamate and dopamine release by potentiating nitric oxide signaling.[12] 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.[13]

Paraxanthine is a competitive nonselective phosphodiesterase inhibitor[14] which raises intracellular cAMP, activates PKA, inhibits TNF-alpha[15][16] and leukotriene[17] synthesis, and reduces inflammation and innate immunity.[17]

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.[18] Similarly, the compound also stimulates increases in calcium ion concentration in muscle.[19]

Pharmacokinetics

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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).

Table 1. Comparative pharmacokinetics of caffeine, and caffeine-derived methylxanthines[20]
Plasma Half-Life

(t1/2; hr)

Volume of Distribution

(Vss,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

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Paraxanthine is a phosphodiesterase type 9 (PDE9) inhibitor and it is sold as a research molecule for this same purpose.[21]

Toxicity

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Paraxanthine is believed to exhibit a lower toxicity than caffeine and the caffeine metabolite, theophylline.[22][23] In a mouse model, intraperitoneal paraxanthine doses of 175 mg/kg/day did not result in animal death or overt signs of stress;[24] by comparison, the intraperitoneal LD50 for caffeine in mice is reported at 168 mg/kg.[25] 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.[26]

As with other methylxanthines, paraxanthine is reported to be teratogenic when administered in high doses;[24] 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.[27]

Paraxanthine was reported to be significantly less clastogenic compared to caffeine or theophylline in an in vitro study using human lymphocytes.[28]

References

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  1. ^ Stavric, B. (1988-01-01). "Methylxanthines: Toxicity to humans. 3. Theobromine, paraxanthine and the combined effects of methylxanthines". Food and Chemical Toxicology. 26 (8): 725–733. doi:10.1016/0278-6915(88)90073-7. ISSN 0278-6915. PMID 3058562.
  2. ^ a b Mazzafera P (May 2004). "Catabolism of caffeine in plants and microorganisms". Frontiers in Bioscience. 9 (1–3): 1348–59. doi:10.2741/1339. PMID 14977550.
  3. ^ Fuhr U, Doehmer J, Battula N, Wölfel C, Flick I, Kudla C, Keita Y, Staib AH (October 1993). "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". Toxicology. 82 (1–3): 169–89. Bibcode:1993Toxgy..82..169F. doi:10.1016/0300-483x(93)90064-y. PMID 8236273.
  4. ^ Guerreiro S, Toulorge D, Hirsch E, Marien M, Sokoloff P, Michel PP (October 2008). "Paraxanthine, the primary metabolite of caffeine, provides protection against dopaminergic cell death via stimulation of ryanodine receptor channels". Molecular Pharmacology. 74 (4): 980–9. doi:10.1124/mol.108.048207. PMID 18621927. S2CID 14842240.
  5. ^ Graham TE, Rush JW, van Soeren MH (June 1994). "Caffeine and exercise: metabolism and performance". Canadian Journal of Applied Physiology. 19 (2): 111–38. doi:10.1139/h94-010. PMID 8081318.
  6. ^ a b Mazzafera P (May 2004). "Catabolism of caffeine in plants and microorganisms". Frontiers in Bioscience. 9 (1–3): 1348–59. doi:10.2741/1339. PMID 14977550.
  7. ^ Summers RM, Mohanty SK, Gopishetty S, Subramanian M (May 2015). "Genetic characterization of caffeine degradation by bacteria and its potential applications". Microbial Biotechnology. 8 (3): 369–78. doi:10.1111/1751-7915.12262. PMC 4408171. PMID 25678373.
  8. ^ a b Caffeine : chemistry, analysis, function and effects. Preedy, Victor R.,, Royal Society of Chemistry (Great Britain). Cambridge, U.K. 2012. ISBN 9781849734752. OCLC 810337257.{{cite book}}: CS1 maint: location missing publisher (link) CS1 maint: others (link)
  9. ^ Daly JW, Jacobson KA, Ukena D (1987). "Adenosine receptors: development of selective agonists and antagonists". Progress in Clinical and Biological Research. 230 (1): 41–63. PMID 3588607.
  10. ^ Müller, Christa E.; Jacobson, Kenneth A. (2011), Fredholm, Bertil B. (ed.), "Xanthines as Adenosine Receptor Antagonists", Methylxanthines, Handbook of Experimental Pharmacology, vol. 200, no. 200, Springer, pp. 151–199, doi:10.1007/978-3-642-13443-2_6, ISBN 978-3-642-13443-2, PMC 3882893, PMID 20859796
  11. ^ Orrú, Marco; Guitart, Xavier; Karcz-Kubicha, Marzena; Solinas, Marcello; Justinova, Zuzana; Barodia, Sandeep Kumar; Zanoveli, Janaina; Cortes, Antoni; Lluis, Carme; Casado, Vicent; Moeller, F. Gerard (April 2013). "Psychostimulant pharmacological profile of paraxanthine, the main metabolite of caffeine in humans". Neuropharmacology. 67C: 476–484. doi:10.1016/j.neuropharm.2012.11.029. ISSN 0028-3908. PMC 3562388. PMID 23261866.
  12. ^ Ferré, Sergi; Orrú, Marco; Guitart, Xavier (2013). "Paraxanthine: Connecting Caffeine to Nitric Oxide Neurotransmission". Journal of Caffeine Research. 3 (2): 72–78. doi:10.1089/jcr.2013.0006. ISSN 2156-5783. PMC 3680978. PMID 24761277.
  13. ^ Orrú, Marco (2013). "Psychostimulant pharmacological profile of paraxanthine, the main metabolite of caffeine in humans". Neuropharmacology. 67C: 476–484. doi:10.1016/j.neuropharm.2012.11.029. PMC 3562388. PMID 23261866.
  14. ^ Essayan DM (November 2001). "Cyclic nucleotide phosphodiesterases". The Journal of Allergy and Clinical Immunology. 108 (5): 671–80. doi:10.1067/mai.2001.119555. PMID 11692087.
  15. ^ Deree J, Martins JO, Melbostad H, Loomis WH, Coimbra R (June 2008). "Insights into the regulation of TNF-alpha production in human mononuclear cells: the effects of non-specific phosphodiesterase inhibition". Clinics. 63 (3): 321–8. doi:10.1590/S1807-59322008000300006. PMC 2664230. PMID 18568240.
  16. ^ Marques LJ, Zheng L, Poulakis N, Guzman J, Costabel U (February 1999). "Pentoxifylline inhibits TNF-alpha production from human alveolar macrophages". American Journal of Respiratory and Critical Care Medicine. 159 (2): 508–11. doi:10.1164/ajrccm.159.2.9804085. PMID 9927365.
  17. ^ a b Peters-Golden M, Canetti C, Mancuso P, Coffey MJ (January 2005). "Leukotrienes: underappreciated mediators of innate immune responses". Journal of Immunology. 174 (2): 589–94. doi:10.4049/jimmunol.174.2.589. PMID 15634873.
  18. ^ Hawke TJ, Willmets RG, Lindinger MI (November 1999). "K+ transport in resting rat hind-limb skeletal muscle in response to paraxanthine, a caffeine metabolite". Canadian Journal of Physiology and Pharmacology. 77 (11): 835–43. doi:10.1139/y99-095. PMID 10593655.
  19. ^ Hawke TJ, Allen DG, Lindinger MI (December 2000). "Paraxanthine, a caffeine metabolite, dose dependently increases [Ca(2+)](i) in skeletal muscle". Journal of Applied Physiology. 89 (6): 2312–7. doi:10.1152/jappl.2000.89.6.2312. PMID 11090584. S2CID 11369121.
  20. ^ Lelo, A.; Birkett, D. J.; Robson, R. A.; Miners, J. O. (August 1986). "Comparative pharmacokinetics of caffeine and its primary demethylated metabolites paraxanthine, theobromine and theophylline in man". British Journal of Clinical Pharmacology. 22 (2): 177–182. doi:10.1111/j.1365-2125.1986.tb05246.x. ISSN 0306-5251. PMC 1401099. PMID 3756065.
  21. ^ "Paraxanthine" (PDF).
  22. ^ Neal L. Benowitz; Peyton Jacob; Haim Mayan; Charles Denaro (1995). "Sympathomimetic effects of paraxanthine and caffeine in humans". Clinical Pharmacology & Therapeutics. 58 (6): 684–691. doi:10.1016/0009-9236(95)90025-X. PMID 8529334. S2CID 22747642.
  23. ^ Institute of Medicine (US) Committee on Military Nutrition Research (2001). Caffeine for the Sustainment of Mental Task Performance: Formulations for Military Operations. Washington (DC): National Academies Press (US). ISBN 978-0-309-08258-7. PMID 25057583.
  24. ^ a b York, R. G.; Randall, J. L.; Scott, W. J. (1986). "Teratogenicity of paraxanthine (1,7-dimethylxanthine) in C57BL/6J mice". Teratology. 34 (3): 279–282. doi:10.1002/tera.1420340307. ISSN 0040-3709. PMID 3798364.
  25. ^ Registry of Toxic Effects of Chemical Substances. National Institute for Occupational Safety and Health. 1987.
  26. ^ Gressner, Olav A.; Lahme, Birgit; Siluschek, Monika; Gressner, Axel M. (2009). "Identification of paraxanthine as the most potent caffeine-derived inhibitor of connective tissue growth factor expression in liver parenchymal cells". Liver International. 29 (6): 886–897. doi:10.1111/j.1478-3231.2009.01987.x. ISSN 1478-3231. PMID 19291178. S2CID 32926935.
  27. ^ Nakatsuka, Toshio; Hanada, Satoshi; Fujii, Takaaki (1983). "Potentiating effects of methylxanthines on teratogenicity of mitomycin C in mice". Teratology. 28 (2): 243–247. doi:10.1002/tera.1420280214. ISSN 1096-9926. PMID 6417813.
  28. ^ Weinstein, David; Mauer, Irving; Katz, Marion L.; Kazmer, Sonja (1975). "The effect of methylxanthines on chromosomes of human lymphocytes in culture". Mutation Research/Environmental Mutagenesis and Related Subjects. 31 (1): 57–61. doi:10.1016/0165-1161(75)90064-3. ISSN 0165-1161. PMID 1128545.
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