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{{Short description|Bitter alkaloid of the cacao plant}}{{cs1 config|name-list-style=vanc|display-authors=6}}{{Distinguish|bromine}}

factoids

LELO A, BIRKETT DJ, ROBSON RA, MINERS JO JOURNAL = BRITISH JOURNAL OF CLINICAL PHARMACOLOGY ISSUE = 2 DATE = AUGUST 1986 PMC = 1401099, 10.1111/j.1365-2125.1986.tb05246.x, Kidney>Renal (10% unchanged, rest as metabolites)correct|CAS}}| CAS_number = 83-67-0| ATC_prefix = C03| ATC_suffix = BD01R03|DA07}}| PubChem = 5429correct|drugbank}}| DrugBank = DB01412correct|chemspider}}| ChemSpiderID = 5236correct|FDA}}| UNII = OBD445WZ5Pcorrect|kegg}}| KEGG = C07480correct|EBI}}| ChEBI = 28946correct|EBI}}| ChEMBL = 1114| C = 7| H = 8| N = 4| O = 2| chemical_formula_ref = | smiles = Cn1cnc2c1c(=O)[nH]c(=O)n2Ccorrect|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)correct|chemspider}}| StdInChIKey = YAPQBXQYLJRXSA-UHFFFAOYSA-N| synonyms = xantheosediurobromine3,7-dimethylxanthine3,7-dihydro-3,7-dimethyl-1H-purine-2,6-dione}}{{Chembox| ImageFile = | ImageSize = | ImageAlt = | IUPACName = | OtherNames = |Section1={{Chembox Identifiers| CASNo = | PubChem = | SMILES = }}|Section2={{Chembox Properties| Formula = | MolarMass =| Appearance = white solid| Density = 1.524 g/cm3| MeltingPtC = 351| BoilingPt = | Solubility = 330 mg/L)}}|Section3={{Chembox Hazards| MainHazards = | FlashPt = | AutoignitionPt = }}}}Theobromine, also known as xantheose, is the principal alkaloid of Theobroma cacao (cacao plant).WEB, Theobromine,weblink PubChem, US National Library of Medicine, 3 September 2022, 27 August 2022, Theobromine is slightly water-soluble (330 mg/L) with a bitter taste.BOOK, Smit HJ, Theobromine and the Pharmacology of Cocoa, Methylxanthines, Handbook of Experimental Pharmacology, 200, 201–234, 2011, 20859797, 10.1007/978-3-642-13443-2_7, 978-3-642-13442-5, In industry, theobromine is used as an additive and precursor to some cosmetics. It is found in chocolate, as well as in a number of other foods, including the leaves of the tea plant, and the kola nut. It is a white or colourless solid, but commercial samples can appear yellowish.

Structure

Theobromine is a flat molecule,JOURNAL, 10.1107/S0108270198009469, Methylxanthines. II. Anhydrous Theobromine, 1998, Ford KA, Ebisuzaki Y, Boyle PD, Acta Crystallographica Section C Crystal Structure Communications, 54, 12, 1980–1983, 1998AcCrC..54.1980F, a derivative of purine. It is also classified as a dimethyl xanthine.BOOK, Environment and Behavior, Baer DM, Pinkston EM, 1997, Westview Press, 200, 978-0813331591,weblink Related compounds include theophylline, caffeine, paraxanthine, and 7-methylxanthine, each of which differ in the number or placement of the methyl groups.

History

Theobromine was first discovered in 1841BOOK, von Bibra E, Ott J, Plant Intoxicants: A Classic Text on the Use of Mind-Altering Plants,weblink 1995, Inner Traditions / Bear & Co, 978-0-89281-498-5, 67–, 2015-12-12, 2019-09-18,weblink live, in cacao beans by the chemist A. Woskresensky.JOURNAL, Woskresensky A, 1842, Über das Theobromin,weblink Liebigs Annalen der Chemie und Pharmacie, 41, 125–127, 10.1002/jlac.18420410117, 2015-12-12, 2016-06-10,weblink live, Synthesis of theobromine from xanthine was first reported in 1882 by Hermann Emil Fischer.BOOK, Essays in Historical Chemistry,weblink Thorpe TE, 1902, The MacMillan Company, JOURNAL, Fischer, Emil, 1882, Umwandlung des Xanthin in Theobromin und Caffein, Berichte der Deutschen Chemischen Gesellschaft, 15, 1, 453–456, 10.1002/cber.18820150194,weblink 2019-09-09, 2019-05-05,weblink live,

Etymology

Theobromine is derived from Theobroma, the name of the genus of the cacao tree, with the suffix -ine given to alkaloids and other basic nitrogen-containing compounds.BOOK, -ine, The American Heritage Dictionary of the English Language, Fourth Edition, Houghton Mifflin Company, 2004,weblink 978-0-395-71146-0, 2007-02-23, 2016-03-03,weblink" title="web.archive.org/web/20160303171459weblink">weblink live, That name in turn is made up of the Greek roots theo ("god") and broma ("food"), meaning "food of the gods".BOOK, Bennett AW, Bealer BK, The World of Caffeine: The Science and Culture of the World's Most Popular Drug, Routledge, New York, 2002, 978-0-415-92723-9,weblink (note: the book incorrectly states that the name "theobroma" is derived from Latin)Despite its name, the compound contains no bromine, which is based on Greek bromos ("stench").

Sources

Theobromine is the primary alkaloid found in cocoa and chocolate. Cocoa butter only contains trace amounts of theobromine. There are usually higher concentrations in dark than in milk chocolate.WEB,weblink AmerMed cocoa extract with 10% theobromine, AmerMed, 2008-04-13, 2015-08-11,weblink" title="web.archive.org/web/20150811092221weblink">weblink dead, There are approximately {{Convert|60|mg|abbr = off|0}} of theobromine in {{Convert|1|oz|order = flip}} of milk chocolate,WEB,weblink USDA Nutrient database, entries for milk chocolate, 2012-12-29, 2017-07-08,weblink dead, while the same amount of dark chocolate contains about {{Convert|200|mg|abbr = off|0}}.WEB,weblink USDA Nutrient database, entries for dark chocolate, 2012-11-07, Cocoa beans naturally contain approximately 1% theobromine.JOURNAL, Kuribara H, Tadokoro S, Behavioral effects of cocoa and its main active compound theobromine: evaluation by ambulatory activity and discrete avoidance in mice, Arukoru Kenkyu to Yakubutsu Izon = Japanese Journal of Alcohol Studies & Drug Dependence, 27, 2, 168–179, April 1992, 1586288, Plant species and components with substantial amounts of theobromine are:WEB,weblink Theobromine content in plant sources, Dr. Duke's Phytochemical and Ethnobotanical Databases, United States Department of Agriculture, 6 February 2019, 9 March 2019, 8 May 2019,weblink dead,

• Theobroma cacao – seed and seed coat
• Theobroma bicolor – seed coat
• Ilex paraguariensis – leaf
• Camellia sinensis – leaf

Theobromine can also be found in trace amounts in the kola nut, the guarana berry, yerba mate (Ilex paraguariensis), Ilex vomitoria, Ilex guayusa,JOURNAL, Schuster J, Mitchell ES, More than just caffeine: psychopharmacology of methylxanthine interactions with plant-derived phytochemicals, Progress in Neuro-Psychopharmacology & Biological Psychiatry, 89, 263–274, March 2019, 30213684, 10.1016/j.pnpbp.2018.09.005, 52274913, free, and the tea plant.BOOK, Prance G, Nesbitt M, The Cultural History of Plants, Routledge, 2004, New York, 137, 175, 178–180, 978-0-415-92746-8, The mean theobromine concentrations in cocoa and carob products are:WEB, FoodData Central,weblink fdc.nal.usda.gov, JOURNAL, Craig WJ, Nguyen TT, 1984, Caffeine and theobromine levels in cocoa and carob products, Journal of Food Science, 49, 1, 302–303, 10.1111/j.1365-2621.1984.tb13737.x, Mean theobromine and caffeine levels respectively, were 0.695 mg/g and 0.071 mg/g in cocoa cereals; 1.47 mg/g and 0.152 mg/g in chocolate bakery products; 1.95 mg/g and 0.138 mg/g in chocolate toppings; 2.66 mg/g and 0.208 mg/g in cocoa beverages; 0.621 mg/g and 0.032 mg/g in chocolate ice creams; 0.226 mg/g and 0.011 mg/g in chocolate milks; 74.8 mg/serving and 6.5 mg/serving in chocolate puddings.... Theobromine and caffeine levels in carob products ranged from 0–0.504 mg/g and 0-0.067 mg/g, respectively., {| class="wikitable"|+! Item! Mean theobromine per 100 g| Cocoa powder| 2060 mgCocoa (beverage)>Cocoa beverages| 266 mg| Chocolate toppings| 195 mg| Chocolate bakery products| 147 mg| Cocoa cereals| 69.5 mg| Chocolate ice creams| 62.1 mg| Chocolate milks| 22.6 mg| Carob products| 0.00–50.4 mg

Biosynthesis

Theobromine is a purine alkaloid derived from xanthosine, a nucleoside. Cleavage of the ribose and N-methylation yields 7-methylxanthosine. 7-Methylxanthosine in turn is the precursor to theobromine, which in turn is the precursor to caffeine.BOOK, Ashihara H, Yokota T, Crozier A, New Light on Alkaloid Biosynthesis and Future Prospects, 2013, Biosynthesis and catabolism of purine alkaloids, Advances in Botanical Research, 68, 111–138, 10.1016/B978-0-12-408061-4.00004-3, 9780124080614,

Pharmacology

File:Caffeine metabolites.svg|thumb|250px|Caffeine is metabolized in the liver into three primary metabolites:paraxanthine (84%), theobromine (12%), and date=August 2019}}|alt=A diagram featuring 4 skeletal chemical formulas. Top (caffeine) relates to similar compounds paraxanthine, theobromine and theophylline.Even without dietary intake, theobromine may occur in the body as it is a product of the human metabolism of caffeine, which is metabolised in the liver into 12% theobromine, 4% theophylline, and 84% paraxanthine.WEB, Caffeine, The Pharmacogenetics and Pharmacogenomics Knowledge Base,weblink 2011-01-08, 2010-11-24,weblink" title="web.archive.org/web/20101124155701weblink">weblink dead, In the liver, theobromine is metabolized into xanthine and subsequently into methyluric acid.JOURNAL, Cornish HH, Christman AA, A study of the metabolism of theobromine, theophylline, and caffeine in man, The Journal of Biological Chemistry, 228, 1, 315–323, September 1957, 10.1016/S0021-9258(18)70714-X, 13475320, free, Important enzymes include CYP1A2 and CYP2E1.JOURNAL, Gates S, Miners JO, Cytochrome P450 isoform selectivity in human hepatic theobromine metabolism, British Journal of Clinical Pharmacology, 47, 3, 299–305, March 1999, 10215755, 2014222, 10.1046/j.1365-2125.1999.00890.x, The elimination half life of theobromine is between 6 and 8 hours.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.JOURNAL, Mumford GK, Benowitz NL, Evans SM, Kaminski BJ, Preston KL, Sannerud CA, Silverman K, Griffiths RR, Absorption rate of methylxanthines following capsules, cola and chocolate, European Journal of Clinical Pharmacology, 51, 3–4, 319–325, 1 December 1996, 9010706, 10.1007/s002280050205, 8405909, The primary mechanism of action for theobromine inside the body is inhibition of adenosine receptors. Its effect as a phosphodiesterase inhibitorJOURNAL, Essayan DM, Cyclic nucleotide phosphodiesterases, The Journal of Allergy and Clinical Immunology, 108, 5, 671–680, November 2001, 11692087, 10.1067/mai.2001.119555, free, is thought to be small.

Effects

{{see also|Theobromine poisoning}}

Humans

Theobromine has no significant stimulant effect on the human central nervous system. It is a bronchodilator and causes relaxation of vascular smooth muscle. It is not currently used as a prescription drug. The amount of theobromine found in chocolate is small enough that chocolate can, in general, be safely consumed by humans.Compared with caffeine, theobromine is weaker in both its inhibition of cyclic nucleotide phosphodiesterases and its antagonism of adenosine receptors.BOOK, Hardman J, Limbird L, Goodman & Gilman's the pharmacological basis of therapeutics, 10th ed., McGraw-Hill, New York, 2001, 745, 978-0-07-135469-1, The potential phosphodiesterase inhibitory effect of theobromine is seen only at amounts much higher than what people normally would consume in a typical diet including chocolate.WEB,weblink Theobromine, DrugBank.ca, 3 November 2018, 13 November 2018,weblink dead,

Toxicity

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 mg/day.WEB,weblink 3,7-Dimethylxanthine (Theobromine), Toxnet, US National Library of Medicine, 1 December 2017, 13 November 2018, 7 October 2018,weblink live, Also, chocolate may be a factor for heartburn in some people because theobromine may affect the esophageal sphincter muscle in a way that permits stomach acids to enter the esophagus.JOURNAL, Latif R, Chocolate/cocoa and human health: a review, The Netherlands Journal of Medicine, 71, 2, 63–68, March 2013, 23462053,weblink

Animals

Theobromine is the reason chocolate is poisonous to dogs. Dogs and other animals that metabolize theobromine (found in chocolate) more slowlyWEB,weblink Chocolate – Toxicology – Merck Veterinary Manual, 23 December 2017, 12 July 2014,weblink" title="web.archive.org/web/20140712005049weblink">weblink live, can succumb to theobromine poisoning from as little as {{cvt|50|g|oz}} of milk chocolate for a smaller dog and {{cvt|400|g|oz}}, or around nine {{convert|1.55|oz|order=flip|adj=on}} small milk chocolate bars, for an average-sized dog. The concentration of theobromine in dark chocolates (about {{cvt|10|g/kg}}) is up to 10 times that of milk chocolate ({{cvt|1|to|5|g/kg}}), meaning dark chocolate is far more toxic to dogs per unit weight or volume than milk chocolate.The median lethal dose of theobromine for dogs is {{cvt|100|–|200|mg/kg|}}; therefore, a {{cvt|10|kg|}} dog would need to consume a minimum of {{cvt|200|g|}} of the most theobromine-rich ({{cvt|5|g/kg|}}) dark chocolate, or a maximum of {{cvt|1|kg|}} (of theobromine-rich milk chocolate), to have a 50% chance of receiving a lethal dose. However, even {{cvt|40|g|}} of milk chocolate may induce vomiting and diarrhea.WEB, Gwaltney-Brant, Sharon, Chocolate Toxicosis in Animals,weblink Merck Veterinary Manual, Merck & Co., Inc., 24 December 2023, The same risk is reported for cats as well,WEB,weblink Chocolate intoxication, Gwaltney-Brant S, American Society for the Prevention of Cruelty to Animals, ASPCA, aspcapro.org, 23 December 2017, 8 February 2017,weblink" title="web.archive.org/web/20170208145634weblink">weblink dead, although cats are less likely to ingest sweet food, as cats lack sweet taste receptors.MAGAZINE,weblink The Poisonous Chemistry of Chocolate, 14 February 2013, Wired (magazine), Wired, 12 March 2017, 8 February 2017,weblink live, Complications include digestive issues, dehydration, excitability, and a slow heart rate. Later stages of theobromine poisoning include epileptic-like seizures and death. If caught early on, theobromine poisoning is treatable.NEWS, HEALTH WATCH: How to Avoid a Canine Chocolate Catastrophe!, The News Letter, Belfast, Northern Ireland, 2005-03-01, Although not common, the effects of theobromine poisoning can be fatal.

See also

• Health effects of chocolate
• History of chocolate
• Theodrenaline

References

{{Reflist}}{{Commons category|Theobromine}}{{Chocolate}}{{Diuretics}}{{Asthma and copd rx}}{{Adenosinergics}}{{Phosphodiesterase inhibitors}}