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.
Paraxanthine is not known to be produced by plants[1] but is observed in nature as a metaboliteofcaffeine 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]
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]
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]
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]
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]Inin 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]
^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. ISSN0278-6915. PMID3058562.
^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. PMID8236273.
^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. PMID18621927. S2CID14842240.
^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. PMID8081318.
^ abCaffeine : chemistry, analysis, function and effects. Preedy, Victor R.,, Royal Society of Chemistry (Great Britain). Cambridge, U.K. 2012. ISBN9781849734752. OCLC810337257.{{cite book}}: CS1 maint: location missing publisher (link) CS1 maint: others (link)
^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. PMID3588607.
^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, ISBN978-3-642-13443-2, PMC3882893, PMID20859796
^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. PMID9927365.
^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. PMID10593655.
^ abYork, 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. ISSN0040-3709. PMID3798364.
^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. ISSN1478-3231. PMID19291178. S2CID32926935.
^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. ISSN1096-9926. PMID6417813.
^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. ISSN0165-1161. PMID1128545.
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