Theobromine Explained

Watchedfields:changed
Verifiedrevid:622941253
Iupac Name:3,7-dimethyl-1H-purine-2,6-dione
Width:135
Legal Status:In general: Unscheduled.
Dependency Liability:None
Routes Of Administration:Oral
Metabolism:Hepatic demethylation and oxidation
Elimination Half-Life:6–8 hours[1] [2]
Excretion:Renal (10% unchanged, rest as metabolites)
Cas Number:83-67-0
Atc Prefix:C03
Atc Suffix:BD01
Pubchem:5429
Drugbank:DB01412
Chemspiderid:5236
Unii:OBD445WZ5P
Kegg:C07480
Chebi:28946
Chembl:1114
C:7
H:8
N:4
O:2
Smiles:Cn1cnc2c1c(=O)[nH]c(=O)n2C
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:YAPQBXQYLJRXSA-UHFFFAOYSA-N
Synonyms:xantheose
diurobromine
3,7-dimethylxanthine
3,7-dihydro-3,7-dimethyl-1H-purine-2,6-dione

Theobromine, also known as xantheose, is the principal alkaloid of Theobroma cacao (cacao plant).[3] Theobromine is slightly water-soluble (330 mg/L) with a bitter taste.[4] In industry, theobromine is used as an additive and precursor to some cosmetics.[3] It is found in chocolate, as well as in a number of other foods, including tea (Camellia sinensis), some American hollies (yaupon and guayusa) and the kola nut. It is a white or colourless solid, but commercial samples can appear yellowish.[4]

Structure

Theobromine is a flat molecule,[5] a derivative of purine. It is also classified as a dimethyl xanthine.[4] [6] Related compounds include theophylline, caffeine, paraxanthine, and 7-methylxanthine, each of which differ in the number or placement of the methyl groups.[4]

History

Theobromine was first discovered in 1841[7] in cacao beans by the chemist A. Woskresensky.[8] Synthesis of theobromine from xanthine was first reported in 1882 by Hermann Emil Fischer.[9] [10] [11]

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.[12] That name in turn is made up of the Greek roots theo ("god") and broma ("food"), meaning "food of the gods".[13]

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.[14]

There are approximately 60mg of theobromine in 1oz of milk chocolate,[15] while the same amount of dark chocolate contains about 200mg.[16] Cocoa beans naturally contain approximately 1% theobromine.[17]

Plant species and components with substantial amounts of theobromine are:[18] [19]

Theobromine can also be found in trace amounts in the kola nut, the guarana berry, yerba mate (Ilex paraguariensis),[20] and the tea plant.[21]

The mean theobromine concentrations in cocoa and carob products are:[22] [23]

! Item! Mean theobromine per 100 g
Cocoa powder2060 mg
Cocoa beverages266 mg
Chocolate toppings195 mg
Chocolate bakery products147 mg
Cocoa cereals69.5 mg
Chocolate ice creams62.1 mg
Chocolate milks22.6 mg
Carob products0.00–50.4 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.[24]

Pharmacology

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.[25]

In the liver, theobromine is metabolized into xanthine and subsequently into methyluric acid.[26] Important enzymes include CYP1A2 and CYP2E1.[27] 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.[28]

The primary mechanism of action for theobromine inside the body is inhibition of adenosine receptors.[4] Its effect as a phosphodiesterase inhibitor[29] is thought to be small.[4]

Effects

See also: Theobromine poisoning.

Humans

Theobromine has no significant stimulant effect on the human central nervous system.[3] It is a bronchodilator and causes relaxation of vascular smooth muscle.[3] It is not currently used as a prescription drug.[4] 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.[3] [30] 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.[31]

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.[32]

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.[33]

Animals

Theobromine is the reason chocolate is poisonous to dogs. Dogs and other animals that metabolize theobromine (found in chocolate) more slowly[34] can succumb to theobromine poisoning from as little as of milk chocolate for a smaller dog and, or around nine 1.55oz small milk chocolate bars, for an average-sized dog. The concentration of theobromine in dark chocolates (about) is up to 10 times that of milk chocolate, 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 ; therefore, a dog would need to consume a minimum of of the most theobromine-rich dark chocolate, or a maximum of (of theobromine-rich milk chocolate), to have a 50% chance of receiving a lethal dose. However, even of milk chocolate may induce vomiting and diarrhea.[35]

The same risk is reported for cats as well,[36] although cats are less likely to ingest sweet food, as cats lack sweet taste receptors.[37] 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.[38] Although not common, the effects of theobromine poisoning can be fatal.

See also

Notes and References

  1. Drouillard DD, Vesell ES, Dvorchik BH . Studies on theobromine disposition in normal subjects. Alterations induced by dietary abstention from or exposure to methylxanthines . Clinical Pharmacology and Therapeutics . 23 . 3 . 296–302 . March 1978 . 627135 . 10.1002/cpt1978233296 . 10519385 .
  2. Lelo A, Birkett DJ, Robson RA, Miners JO . Comparative pharmacokinetics of caffeine and its primary demethylated metabolites paraxanthine, theobromine and theophylline in man . British Journal of Clinical Pharmacology . 22 . 2 . 177–182 . August 1986 . 3756065 . 1401099 . 10.1111/j.1365-2125.1986.tb05246.x .
  3. Web site: Theobromine . PubChem, US National Library of Medicine . 3 September 2022 . 27 August 2022.
  4. 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 .
  5. 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 .
  6. Book: Environment and Behavior . Baer DM, Pinkston EM . 1997 . Westview Press . 200 . 978-0813331591 .
  7. Book: von Bibra E, Ott J . Plant Intoxicants: A Classic Text on the Use of Mind-Altering Plants. 1995. Inner Traditions / Bear & Co. 978-0-89281-498-5. 67–. 2015-12-12. 2019-09-18. https://web.archive.org/web/20190918203121/https://books.google.com/books?id=EWqhC4djXSQC&pg=PA67. live.
  8. Woskresensky A . 1842 . Über das Theobromin . Liebigs Annalen der Chemie und Pharmacie . 41 . 125–127 . 10.1002/jlac.18420410117 . 2015-12-12 . 2016-06-10 . https://web.archive.org/web/20160610112332/https://books.google.com/books?id=ZE09AAAAcAAJ&pg=PA125 . live .
  9. Book: Essays in Historical Chemistry . Thorpe TE . 1902 . The MacMillan Company .
  10. Fischer, Emil . 1882 . Umwandlung des Xanthin in Theobromin und Caffein . Berichte der Deutschen Chemischen Gesellschaft . 15 . 1 . 453–456 . 10.1002/cber.18820150194 . 2019-09-09 . 2019-05-05 . https://web.archive.org/web/20190505192210/https://zenodo.org/record/1425264/files/article.pdf . live .
  11. Fischer E . 1882. Über Caffein, Theobromin, Xanthin und Guanin . Justus Liebigs Annalen der Chemie . 215 . 3. 253–320 . 10.1002/jlac.18822150302 .
  12. Book: -ine . The American Heritage Dictionary of the English Language, Fourth Edition . . 2004 . http://dictionary.reference.com/browse/-ine . 978-0-395-71146-0 . 2007-02-23 . 2016-03-03 . https://web.archive.org/web/20160303171459/http://dictionary.reference.com/browse/-ine . live .
  13. 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 . (note: the book incorrectly states that the name "theobroma" is derived from Latin)
  14. Web site: AmerMed cocoa extract with 10% theobromine . AmerMed . 2008-04-13 . 2015-08-11 . https://web.archive.org/web/20150811092221/http://amermed.com/cocoa.htm . dead .
  15. Web site: USDA Nutrient database, entries for milk chocolate . 2012-12-29 . 2017-07-08 . https://web.archive.org/web/20170708121554/https://ndb.nal.usda.gov/ndb/foods/show/5924?qlookup=milk+chocolate&offset=&format=Full#id-1 . dead .
  16. Web site: USDA Nutrient database, entries for dark chocolate . 2012-11-07 .
  17. 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 .
  18. Web site: 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. https://web.archive.org/web/20190508200500/https://phytochem.nal.usda.gov/phytochem/chemicals/show/17073?et=. dead.
  19. Crown PL, Emerson TE, Gu J, Hurst WJ, Pauketat TR, Ward T . August 2012 . Ritual Black Drink consumption at Cahokia . Proc. Natl. Acad. Sci. U.S.A. . 109 . 35 . 13944–9 . 10.1073/pnas.1208404109 . 3435207 . 22869743 . free.
  20. 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 .
  21. Book: Prance G, Nesbitt M . The Cultural History of Plants . Routledge . 2004 . New York . 137, 175, 178–180 . 978-0-415-92746-8.
  22. Web site: FoodData Central . fdc.nal.usda.gov.
  23. 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..
  24. 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 .
  25. Web site: Caffeine . The Pharmacogenetics and Pharmacogenomics Knowledge Base . 2011-01-08 . 2010-11-24 . https://web.archive.org/web/20101124155701/http://www.pharmgkb.org/do/serve?objId=PA448710&objCls=Drug#tabview=tab1 . dead .
  26. 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 .
  27. 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 .
  28. 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 .
  29. 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 .
  30. 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.
  31. Web site: Theobromine. DrugBank.ca. 3 November 2018. 13 November 2018. https://web.archive.org/web/20181113075732/https://www.drugbank.ca/drugs/DB01412. dead.
  32. Web site: 3,7-Dimethylxanthine (Theobromine). Toxnet, US National Library of Medicine. 1 December 2017. 13 November 2018. 7 October 2018. https://web.archive.org/web/20181007145619/https://toxnet.nlm.nih.gov/cgi-bin/sis/search2/r?dbs+hsdb:@term+@DOCNO+7332#permalink. live.
  33. Latif R . Chocolate/cocoa and human health: a review . The Netherlands Journal of Medicine . 71 . 2 . 63–68 . March 2013 . 23462053 .
  34. Web site: Chocolate – Toxicology – Merck Veterinary Manual. 23 December 2017. 12 July 2014. https://web.archive.org/web/20140712005049/http://www.merckmanuals.com/vet/toxicology/food_hazards/chocolate.html. live.
  35. Web site: Gwaltney-Brant . Sharon . Chocolate Toxicosis in Animals . Merck Veterinary Manual . Merck & Co., Inc. . 24 December 2023.
  36. Web site: Chocolate intoxication . Gwaltney-Brant S . . aspcapro.org . 23 December 2017 . 8 February 2017 . https://web.archive.org/web/20170208145634/http://aspcapro.org/sites/pro/files/m-toxbrief_0201_0.pdf . dead.
  37. The Poisonous Chemistry of Chocolate . 14 February 2013 . . 12 March 2017 . 8 February 2017 . https://web.archive.org/web/20170208145832/https://www.wired.com/2013/02/the-poisonous-nature-of-chocolate/ . live.
  38. News: HEALTH WATCH: How to Avoid a Canine Chocolate Catastrophe! . The News Letter . Belfast, Northern Ireland . 2005-03-01.

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