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Paraxanthine
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<h2 id="production-and-metabolism">Production and metabolism</h2> <p>Paraxanthine is not known to be produced by plants<a class="footnote-ref" id="fnref:1" href="#fn:1"><sup>1</sup></a> but is observed in nature as a <a href="/facts/Metabolite/nAyywVtA">metabolite</a> of <a href="/facts/Caffeine/Hx6E2QC5">caffeine</a> in animals and some species of bacteria.<a class="footnote-ref" id="fnref:2" href="#fn:2"><sup>2</sup></a> </p><p>Paraxanthine is the primary metabolite of caffeine in humans and other animals, such as mice.<a class="footnote-ref" id="fnref:3" href="#fn:3"><sup>3</sup></a> Shortly after ingestion, roughly 84% of caffeine is metabolized into paraxanthine by <a href="/facts/Cytochrome_P450/alxusFD0">hepatic cytochrome P450</a>, which removes a methyl group from the N3 position of caffeine.<a class="footnote-ref" id="fnref:4" href="#fn:4"><sup>4</sup></a><a class="footnote-ref" id="fnref:5" href="#fn:5"><sup>5</sup></a><a class="footnote-ref" id="fnref:6" href="#fn:6"><sup>6</sup></a> After formation, paraxanthine can be broken down to <a href="/facts/7-methylxanthine/GGFSnAmR">7-methylxanthine</a> by demethylation of the N1 position,<a class="footnote-ref" id="fnref:7" href="#fn:7"><sup>7</sup></a> which is subsequently demethylated into xanthine or oxidized by CYP2A6 and CYP1A2 into 1,7-dimethyluric acid.<a class="footnote-ref" id="fnref:8" href="#fn:8"><sup>8</sup></a> 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.<a class="footnote-ref" id="fnref:9" href="#fn:9"><sup>9</sup></a> 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.<a class="footnote-ref" id="fnref:10" href="#fn:10"><sup>10</sup></a> </p><p>Certain proposed synthetic pathways of caffeine make use of paraxanthine as a bypass intermediate. However, its absence in plant <a href="/facts/Alkaloid/m6hUXohz">alkaloid</a> assays implies that these are infrequently, if ever, directly produced by plants. </p> <h2 id="pharmacology-and-physiological-effects">Pharmacology and physiological effects</h2> <p>Like caffeine, paraxanthine is a <a href="/facts/Psychoactive/dNXrUmsx">psychoactive</a> <a href="/facts/Central_nervous_system/k8I6To97">central nervous system</a> (CNS) <a href="/facts/Stimulant/nmBdAXM5">stimulant</a>.<a class="footnote-ref" id="fnref:11" href="#fn:11"><sup>11</sup></a> </p> <h3>Pharmacodynamics</h3> <p>Studies indicate that, similar to caffeine, simultaneous antagonism of <a href="/facts/Adenosine_receptor/TjlLlUD0">adenosine receptors</a><a class="footnote-ref" id="fnref:12" href="#fn:12"><sup>12</sup></a> is responsible for paraxanthine's stimulatory effects. Paraxanthine adenosine receptor binding affinity (21 μM for <a href="/facts/Adenosine_A1_receptor/achlkhqG">A1</a>, 32 μM for <a href="/facts/Adenosine_A2A_receptor/vds2yBur">A2A</a>, 4.5 μM for <a href="/facts/Adenosine_A2B_receptor/SyFwMu1T">A2B</a>, and >100 for μM for <a href="/facts/Adenosine_A3_receptor/uJJqaTvW">A3</a>) is similar or slightly stronger than caffeine, but weaker than theophylline.<a class="footnote-ref" id="fnref:13" href="#fn:13"><sup>13</sup></a> </p><p>Paraxanthine is a selective inhibitor of cGMP-preferring <a href="/facts/Phosphodiesterase/zRdFKnKH">phosphodiesterase</a> (PDE9) activity<a class="footnote-ref" id="fnref:14" href="#fn:14"><sup>14</sup></a> and is hypothesized to increase glutamate and <a href="/facts/Dopamine/5gNy8Xkd">dopamine</a> release by potentiating nitric oxide signaling.<a class="footnote-ref" id="fnref:15" href="#fn:15"><sup>15</sup></a> Activation of a nitric oxide-<a href="/facts/Cyclic_guanosine_monophosphate/zsge65d9">cGMP</a> pathway may be responsible for some of the behavioral effects of paraxanthine that differ from those associated with caffeine.<a class="footnote-ref" id="fnref:16" href="#fn:16"><sup>16</sup></a> </p><p>Paraxanthine is a competitive nonselective <a href="/facts/Phosphodiesterase_inhibitor/QIXRfPcb">phosphodiesterase inhibitor</a><a class="footnote-ref" id="fnref:17" href="#fn:17"><sup>17</sup></a> which raises intracellular <a href="/facts/Cyclic_adenosine_monophosphate/flK2vwUe">cAMP</a>, activates <a href="/facts/CAMP-dependent_protein_kinase/kaKoYfbp">PKA</a>, <a href="/facts/TNF_inhibitor/LS7R0oA1">inhibits TNF-alpha</a><a class="footnote-ref" id="fnref:18" href="#fn:18"><sup>18</sup></a><a class="footnote-ref" id="fnref:19" href="#fn:19"><sup>19</sup></a> and <a href="/facts/Leukotriene/PxNEg3IS">leukotriene</a><a class="footnote-ref" id="fnref:20" href="#fn:20"><sup>20</sup></a> synthesis, and <a href="/facts/Anti-inflammatory/W27poSUd">reduces inflammation</a> and <a href="/facts/Innate_immunity/lz4BpSQI">innate immunity</a>.<a class="footnote-ref" id="fnref:21" href="#fn:21"><sup>21</sup></a> </p><p>Unlike <a href="/facts/Caffeine/Hx6E2QC5">caffeine</a>, paraxanthine acts as an enzymatic effector of Na+/K+ <a href="/facts/ATPase/8aEJlNgl">ATPase</a>. As a result, it is responsible for increased transport of <a href="/facts/Potassium/FWPwS7Rj">potassium</a> ions into skeletal muscle tissue.<a class="footnote-ref" id="fnref:22" href="#fn:22"><sup>22</sup></a> Similarly, the compound also stimulates increases in <a href="/facts/Calcium/hf252CC0">calcium</a> ion concentration in muscle.<a class="footnote-ref" id="fnref:23" href="#fn:23"><sup>23</sup></a> </p> <h3>Pharmacokinetics</h3> <p>The <a href="/facts/Pharmacokinetic/x4CUUnle">pharmacokinetic</a> 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. </p> Comparative pharmacokinetics of caffeine and caffeine-derived methylxanthines<a class="footnote-ref" id="fnref:24" href="#fn:24"><sup>24</sup></a><table><tbody><tr><th></th><th><a href="/facts/Biological_half-life/7nB2JtMr">Plasma half-life</a><p>(t1/2; hr)</p></th><th>Volume of distribution<p>(Vss,unbound; l/kg)</p></th><th>Plasma clearance<p>(CL; ml/min/kg)</p></th></tr><tr><td><a href="/facts/Caffeine/Hx6E2QC5">Caffeine</a></td><td>4.1 ± 1.3</td><td>1.06 ± 0.26</td><td>2.07 ± 0.96</td></tr><tr><td>Paraxanthine</td><td>3.1 ± 0.8</td><td>1.18 ± 0.37</td><td>2.20 ± 0.91</td></tr><tr><td><a href="/facts/Theobromine/1L7mWzQ4">Theobromine</a></td><td>7.2 ± 1.6</td><td>0.79 ± 0.15</td><td>1.20 ± 0.40</td></tr><tr><td><a href="/facts/Theophylline/qJzjQVB2">Theophylline</a></td><td>6.2 ± 1.4</td><td>0.77 ± 0.17</td><td>0.93 ± 0.22</td></tr></tbody></table> <h3>Uses</h3> <p>Paraxanthine is a phosphodiesterase type 9 (PDE9) inhibitor and it is sold as a research molecule for this same purpose.<a class="footnote-ref" id="fnref:25" href="#fn:25"><sup>25</sup></a> </p> <h2 id="toxicity">Toxicity</h2> <p>Paraxanthine is believed to exhibit a lower <a href="/facts/Toxicity/qa96rs60">toxicity</a> than caffeine and the caffeine metabolite, <a href="/facts/Theophylline/qJzjQVB2">theophylline</a>.<a class="footnote-ref" id="fnref:26" href="#fn:26"><sup>26</sup></a><a class="footnote-ref" id="fnref:27" href="#fn:27"><sup>27</sup></a> In a mouse model, intraperitoneal paraxanthine doses of 175 mg/kg/day did not result in animal death or overt signs of stress;<a class="footnote-ref" id="fnref:28" href="#fn:28"><sup>28</sup></a> by comparison, the intraperitoneal <a href="/facts/Median_lethal_dose/PSTer8Wv">LD50</a> for caffeine in mice is reported at 168 mg/kg.<a class="footnote-ref" id="fnref:29" href="#fn:29"><sup>29</sup></a> In <i>in vitro</i> 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.<a class="footnote-ref" id="fnref:30" href="#fn:30"><sup>30</sup></a> </p><p>As with other methylxanthines, paraxanthine is reported to be <a href="/facts/Teratogenic/j4BN6lsB">teratogenic</a> when administered in high doses;<a class="footnote-ref" id="fnref:31" href="#fn:31"><sup>31</sup></a> 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 <a href="/facts/Mitomycin_C/7ug46Xh5">mitomycin C</a>, but not for paraxanthine coadministered with mitomycin C.<a class="footnote-ref" id="fnref:32" href="#fn:32"><sup>32</sup></a> </p><p>Paraxanthine was reported to be significantly less <a href="/facts/Clastogen/RqehKbBG">clastogenic</a> compared to caffeine or theophylline in an <i>in vitro</i> study using human lymphocytes.<a class="footnote-ref" id="fnref:33" href="#fn:33"><sup>33</sup></a> </p> <h2 id="external-links">External links</h2> <ul><li> Media related to Paraxanthine at Wikimedia Commons</li></ul> <h2 id="references">References</h2> <ol> <li id="fn:1"><p>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. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:1" class="footnote-back-ref">↩</a></p></li> <li id="fn:2"><p>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. <a href="https://doi.org/10.2741%2F1339" target="_blank">https://doi.org/10.2741%2F1339</a> <a href="#fnref:2" class="footnote-back-ref">↩</a></p></li> <li id="fn:3"><p>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. <a href="/wiki/Bibcode_(identifier)" target="_blank">/wiki/Bibcode_(identifier)</a> <a href="#fnref:3" class="footnote-back-ref">↩</a></p></li> <li id="fn:4"><p>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. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:4" class="footnote-back-ref">↩</a></p></li> <li id="fn:5"><p>Graham TE, Rush JW, van Soeren MH (June 1994). "Caffeine and exercise: metabolism and performance". 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