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
UNII
Properties
C7H8N4O2
Molar mass 180.17 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).
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Infobox references

Paraxanthine, or 1,7-dimethylxanthine, is a dimethyl derivative of xanthine, structurally related to caffeine. Like caffeine, paraxanthine is a psychoactive central nervous system (CNS) stimulant.][1] It possesses a potency roughly equal to that of caffeine and is likely involved in the mediation of the effects of caffeine itself.

Production and metabolism[edit]

Paraxanthine is not produced by plants[citation needed] and is only observed in nature as a metabolite of caffeine in animals.Paraxanthine is also a natural metabolite of caffeine in some species of bacteria[1] After intake, roughly 84% of caffeine is demethylated at the 3-position to yield paraxanthine, making it the chief metabolite of caffeine in the body.[2]

Paraxanthine is also a major metabolite of caffeine in humans and other animals, such as mice.[3] Shortly after ingestion, caffeine is metabolized into paraxanthine by hepatic cytochrome P450,[4] which removes a methyl group from the N3 position of caffein.e[5] After formation, paraxanthine can be broken down to 7-methylxanthine by demethylation of the N1 position,[6] which is subsequently demethylated into xanthine or oxidized by CYP2A6 and CYP1A2 into 1,7-dimethylaric acid.[5] 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.[7] 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.[7]

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[edit]

Paraxanthine may be responsible for the lipolytic properties of caffeine, and its presence in the blood causes an increase in serum free fatty acid concentration.[8]

Pharmacodynamics[edit]

Paraxanthine is a competitive nonselective phosphodiesterase inhibitor[9] which raises intracellular cAMP, activates PKA, inhibits TNF-alpha[10][11] and leukotriene[12] synthesis, and reduces inflammation and innate immunity.[12] Paraxanthine is a nonselective adenosine receptor antagonist[13] which raises plasma epinephrine and diastolic blood pressure. Paraxanthine, unlike caffeine, 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.[14] Similarly, the compound also stimulates increases in calcium ion concentration in muscle.[15]

Toxicity[edit]

Paraxanthine is believed to exhibit a lower toxicity than caffeine.[16] While blood levels commensurate with average intake appear to be fairly innocuous, high blood concentrations of paraxanthine have been linked to miscarriage in pregnant mothers.[17]

References[edit]

  1. ^ a b Mazzafera P (May 2004). "Catabolism of caffeine in plants and microorganisms". Frontiers in Bioscience : a Journal and Virtual Library. 9: 1348–59. PMID 14977550.
  2. ^ 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.
  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. doi:10.1016/0300-483x(93)90064-y. PMID 8236273.
  4. ^ Graham TE, Rush JW, van Soeren MH (June 1994). "Caffeine and exercise: metabolism and performance". Canadian Journal of Applied Physiology = Revue Canadienne De Physiologie Appliquee. 19 (2): 111–38. doi:10.1139/h94-010. PMID 8081318.
  5. ^ 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.
  6. ^ 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.
  7. ^ a b Caffeine : chemistry, analysis, function and effects. Preedy, Victor R.,, Royal Society of Chemistry (Great Britain),. Cambridge, U.K. ISBN 9781849734752. OCLC 810337257.
  8. ^ Hetzler RK, Knowlton RG, Somani SM, Brown DD, Perkins RM (January 1990). "Effect of paraxanthine on FFA mobilization after intravenous caffeine administration in humans". Journal of Applied Physiology. 68 (1): 44–7. doi:10.1152/jappl.1990.68.1.44. PMID 2312486.
  9. ^ 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.
  10. ^ 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.
  11. ^ 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.
  12. ^ 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.
  13. ^ 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.
  14. ^ 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.
  15. ^ 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.
  16. ^ 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.
  17. ^ Klebanoff MA, Levine RJ, DerSimonian R, Clemens JD, Wilkins DG (November 1999). "Maternal serum paraxanthine, a caffeine metabolite, and the risk of spontaneous abortion". The New England Journal of Medicine. 341 (22): 1639–44. doi:10.1056/NEJM199911253412202. PMID 10572151.

External links[edit]