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Paraxanthine, also known as 1,7-dimethylxanthine, is an isomer of theophylline and theobromine, two well-known found in coffee, tea, and chocolate, mainly in the form of caffeine. It is a member of the xanthine family of alkaloids, which also includes theophylline and theobromine in addition to caffeine.
Paraxanthine is the primary metabolite of caffeine in humans and other animals, such as mice. 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. After formation, paraxanthine can be broken down to 7-methylxanthine by demethylation of the N1 position, 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. (2025). 9781849734752 ISBN 9781849734752 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.
Paraxanthine is a selective inhibitor of cGMP-preferring phosphodiesterase (PDE9) activity and is hypothesized to increase glutamate and dopamine release by potentiating nitric oxide signaling. 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.
Paraxanthine is a competitive nonselective phosphodiesterase inhibitor which raises intracellular cAMP, activates PKA, TNF inhibitor and leukotriene 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. Similarly, the compound also stimulates increases in calcium ion concentration in muscle.
| +Comparative pharmacokinetics of caffeine and caffeine-derived methylxanthines ! !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 |
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.
Paraxanthine was reported to be significantly less compared to caffeine or theophylline in an in vitro study using human lymphocytes.
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