Theobromine: Difference between revisions

| Watchedfields = changed

| verifiedrevid = 622941253

| IUPAC_name = 3,7-dimethyl-1''H''-purine-2,6-dione

| image = Theobromine.svg

| width = 135

| image2 = Theobromine 3D ball.png

<!--Clinical data-->| legal_status = In general: Unscheduled.

<!--Pharmacokinetic data-->| metabolism = [[Liver|Hepatic]] [[demethylation]] and [[redox|oxidation]]

| excretion = [[Kidney|Renal]] (10% unchanged, rest as metabolites)

<!--Identifiers-->| CAS_number_Ref = {{cascite|correct|CAS}}

<!--Chemical data-->| C = 7

| C=7H | H=8 | N=4 | O=2 8

| smiles = Cn1cnc2c1c(=O)[nH]c(=O)n2C

| StdInChI_Ref = {{stdinchicite|correct|chemspider}}

| StdInChI = 1S/C7H8N4O2/c1-10-3-8-5-4(10)6(12)9-7(13)11(5)2/h3H,1-2H3,(H,9,12,13)

| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

| StdInChIKey = YAPQBXQYLJRXSA-UHFFFAOYSA-N

| synonyms = xantheose<br />diurobromine<br />3,7-dimethylxanthine<br />3,7-dihydro-3,7-dimethyl-1''H''-purine-2,6-dione

'''Theobromine''', also known as '''xantheose''', is the principal [[alkaloid]] of ''[[Theobroma cacao]]'' (cacao plant).<ref name="pubchem">{{cite web |title=Theobromine |url=https://pubchem.ncbi.nlm.nih.gov/compound/5429 |publisher=PubChem, US National Library of Medicine |access-date=3 September 2022 |date=27 August 2022}}</ref> Theobromine is slightly water-[[solubility|soluble]] (330&nbsp;mg/L) with a bitter taste.<ref name=Hbk>{{cite book | vauthors = Smit HJ | chapter = Theobromine and the Pharmacology of Cocoa | title = Methylxanthines | series = Handbook of Experimental Pharmacology | volume = 200 | issue = <!-- none --> | pages = 201–234 | year = 2011 | pmid = 20859797 | doi = 10.1007/978-3-642-13443-2_7 | isbn = 978-3-642-13442-5 }}</ref> In industry, theobromine is used as an [[food additive|additive]] and precursor to some [[cosmetics]].<ref name=pubchem/> It is found in [[chocolate]], as well as in a number of other foods, including the[[tea]] leaves(''[[Camellia ofsinensis]]''), thesome American [[teaHolly|hollies]] plant,([[Ilex vomitoria|yaupon]] and [[Ilex guayusa|guayusa]]) and the [[kola nut]]. It is a white or colourless solid, but commercial samples can appear yellowish.<ref name=Hbk/>

Theobromine is a flat molecule,<ref name=Acta>{{cite journal |doi=10.1107/S0108270198009469|title=Methylxanthines. II. Anhydrous Theobromine |year=1998 | vauthors = Ford KA, Ebisuzaki Y, Boyle PD |journal=Acta Crystallographica Section C Crystal Structure Communications |volume=54 |issue=12 |pages=1980–1983 |bibcode=1998AcCrC..54.1980F }}</ref> a derivative of [[purine]]. It is also classified as a di[[methyl|dimethyl]] [[xanthine]].<ref name=Hbk/><ref name="envbeh-p200">{{cite book | title=Environment and Behavior | vauthors = Baer DM, Pinkston EM | year=1997 | publisher=Westview Press | page=[https://archive.org/details/environmentbehav0000unse/page/200 200] | isbn=978-0813331591 | url=https://archive.org/details/environmentbehav0000unse/page/200 }}</ref> Related compounds include [[theophylline]], [[caffeine]], [[paraxanthine]], and [[7-methylxanthine]], each of which differ in the number or placement of the methyl groups.<ref name=Hbk/>

Theobromine was first discovered in 1841<ref>{{cite book| vauthors = von Bibra E, Ott J |title=Plant Intoxicants: A Classic Text on the Use of Mind-Altering Plants|url=https://books.google.com/books?id=EWqhC4djXSQC&pg=PA67|date=1995|publisher=Inner Traditions / Bear & Co|isbn=978-0-89281-498-5|pages=67–|access-date=2015-12-12|archive-date=2019-09-18|archive-url=https://web.archive.org/web/20190918203121/https://books.google.com/books?id=EWqhC4djXSQC&pg=PA67|url-status=live}}</ref> in cacao beans by athe chemist [[Aleksandr Voskresensky|A. Woskresensky]].<ref>{{cite journal | vauthors = Woskresensky A | year = 1842 | title = Über das Theobromin | url = https://books.google.com/books?id=ZE09AAAAcAAJ&pg=PA125 | journal = Liebigs Annalen der Chemie und Pharmacie | volume = 41 | pages = 125–127 | doi = 10.1002/jlac.18420410117 | access-date = 2015-12-12 | archive-date = 2016-06-10 | archive-url = https://web.archive.org/web/20160610112332/https://books.google.com/books?id=ZE09AAAAcAAJ&pg=PA125 | url-status = live }}</ref> Synthesis of theobromine from [[xanthine]] was first reported in 1882 by [[Hermann Emil Fischer]].<ref name="historicalchemistry">{{cite book | title=Essays in Historical Chemistry | url=https://archive.org/details/b31350975_0002 | vauthors = Thorpe TE | year=1902 | publisher=The MacMillan Company }}</ref><ref>{{cite journal | vauthors = Fischer, Emil | year = 1882 | title = Umwandlung des Xanthin in Theobromin und Caffein | journal = Berichte der Deutschen Chemischen Gesellschaft | volume = 15 | issue = 1 | pages = 453–456 | doi = 10.1002/cber.18820150194 | url = https://zenodo.org/record/1425264 | access-date = 2019-09-09 | archive-date = 2019-05-05 | archive-url = https://web.archive.org/web/20190505192210/https://zenodo.org/record/1425264/files/article.pdf | url-status = live }}</ref><ref>{{ cite journal | vauthors = Fischer E |year=1882| title = Über Caffein, Theobromin, Xanthin und Guanin | url = https://zenodo.org/record/1427381| journal = Justus Liebigs Annalen der Chemie | volume = 215 | issue = 3| pages = 253–320 | doi = 10.1002/jlac.18822150302 }}</ref>

Despite its name, the compound contains no [[bromine]], which is based on Greek ''bromos'' ("stench").{{Cn|date=May 2024}}

Plant species and components with substantial amounts of theobromine are:<ref name="arsgrin-theobromine">{{cite web| url=https://phytochem.nal.usda.gov/phytochem/chemicals/show/17073?et=| title=Theobromine content in plant sources| publisher=Dr. Duke's Phytochemical and Ethnobotanical Databases, [[United States Department of Agriculture]]| date=6 February 2019| access-date=9 March 2019| archive-date=8 May 2019| archive-url=https://web.archive.org/web/20190508200500/https://phytochem.nal.usda.gov/phytochem/chemicals/show/17073?et=| url-status=dead}}</ref><ref name=":4">{{cite journal |vauthors=Crown PL, Emerson TE, Gu J, Hurst WJ, Pauketat TR, Ward T |date=August 2012 |title=Ritual Black Drink consumption at Cahokia |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=109 |issue=35 |pages=13944–9 |doi=10.1073/pnas.1208404109 |pmc=3435207 |pmid=22869743 |doi-access=free}}</ref>

Theobromine can also be found in trace amounts in the [[kola nut]], the [[guarana]] berry, [[yerba mate]] ([[Yerba Mate|''Ilex paraguariensis'']]), ''[[Ilex vomitoria]]'', ''[[Ilex guayusa]]'',<ref>{{cite journal | vauthors = Schuster J, Mitchell ES | title = More than just caffeine: psychopharmacology of methylxanthine interactions with plant-derived phytochemicals | journal = Progress in Neuro-Psychopharmacology & Biological Psychiatry | volume = 89 | pages = 263–274 | date = March 2019 | pmid = 30213684 | doi = 10.1016/j.pnpbp.2018.09.005 | s2cid = 52274913 | doi-access = free }}</ref> and the [[Camellia sinensis|tea plant]].<ref name="culthistplants">{{cite book | vauthors = Prance G, Nesbitt M | title=The Cultural History of Plants | publisher=Routledge | year=2004 | location=New York | pages=137, 175, 178–180 | isbn = 978-0-415-92746-8}}</ref>

Unlike caffeine, which is highly water-soluble, theobromine is only slightly water-soluble and is more fat soluble, and thus peaks more slowly in the blood. While caffeine peaks after only 30 minutes, theobromine requires 2–3 hours to peak.<ref>{{cite journal | vauthors = Mumford GK, Benowitz NL, Evans SM, Kaminski BJ, Preston KL, Sannerud CA, Silverman K, Griffiths RR | display-authors = 6 | title = Absorption rate of methylxanthines following capsules, cola and chocolate | journal = European Journal of Clinical Pharmacology | volume = 51 | issue = 3–4 | pages = 319–325 | date = 1 December 1996 | pmid = 9010706 | doi = 10.1007/s002280050205 | s2cid = 8405909 }}</ref>

The primary mechanism of action for theobromine inside the body is inhibition of [[adenosine]] receptors.<ref name=Hbk/> Its effect as a [[phosphodiesterase inhibitor]]<ref name="PDEs-Essayan">{{cite journal | vauthors = Essayan DM | title = Cyclic nucleotide phosphodiesterases | journal = The Journal of Allergy and Clinical Immunology | volume = 108 | issue = 5 | pages = 671–680 | date = November 2001 | pmid = 11692087 | doi = 10.1067/mai.2001.119555 | doi-access = free }}</ref> is thought to be small.<ref name=Hbk/>

At doses of 0.8–1.5 g/day (50–100 g cocoa), sweating, trembling and severe headaches were noted, with limited mood effects found at 250&nbsp;mg/day.<ref>{{Citecite web|url=https://toxnet.nlm.nih.gov/cgi-bin/sis/search2/r?dbs+hsdb%3A%40term+%40DOCNO+7332#permalink|title=3,7-Dimethylxanthine (Theobromine)|publisher=Toxnet, US National Library of Medicine|date=1 December 2017|access-date=13 November 2018|archive-date=7 October 2018|archive-url=https://web.archive.org/web/20181007145619/https://toxnet.nlm.nih.gov/cgi-bin/sis/search2/r?dbs+hsdb:@term+@DOCNO+7332#permalink|url-status=live}}</ref>

Theobromine is the reason chocolate is poisonous to dogs. Dogs and other animals that [[metabolize]] theobromine (found in chocolate) more slowly<ref>{{cite web|url=http://www.merckmanuals.com/vet/toxicology/food_hazards/chocolate.html|title=Chocolate – Toxicology – Merck Veterinary Manual|access-date=23 December 2017|archive-date=12 July 2014|archive-url=https://web.archive.org/web/20140712005049/http://www.merckmanuals.com/vet/toxicology/food_hazards/chocolate.html|url-status=live}}</ref> can succumb to theobromine poisoning from as little as {{convertcvt|50|g|oz}} of [[milk chocolate]] for a smaller dog and {{convertcvt|400|g|oz}}, or around nine {{Convertconvert|1.55|oz|order = flip|adj = on}} small milk chocolate bars, for an average-sized dog. The concentration of theobromine in dark chocolates (approximatelyabout {{Convertcvt|10|g/kg|abbr = on}}) is up to 10 times that of milk chocolate ({{Convertcvt|1|to|5|g/kg|abbr = on}}) –, meaning dark chocolate is far more toxic to dogs per unit weight or volume than milk chocolate.{{Cn|date=May The lethal dose of theobromine for dogs is 100-500mg/kg, therefore, a 10kg dog would need to consume a minimum of 200g of the most theobromine-rich (5g per kg) milk chocolate, or a maximum of 1kg (of theobromine-rich milk chocolate), to meet the lethal dose.2024}}