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Theobromine
Systematic (IUPAC) name
3,7-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione
Identifiers
CAS number 83-67-0
ATC code C03BD01 R03DA07
PubChem 5429
ChemSpider 5236
Chemical data
Formula C7H8N4O2[1] 
Mol. mass 180.164 g/mol
SMILES eMolecules & PubChem
Synonyms xantheose
diurobromine
3,7-dimethylxanthine
Pharmacokinetic data
Metabolism Hepatic demethylation and oxidation[2]
Half life 7.1 +/- 0.7 hours
Excretion Renal (10% unchanged, rest as metabolites)[2]
Therapeutic considerations
Pregnancy cat.  ?
Legal status Uncontrolled substance
Routes Oral
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Theobromine, also known as xantheose,[1] is a bitter alkaloid of the cacao plant, found in chocolate, as well as in a number of other foods, including the leaves of the tea plant, and the kola or cola nut. It is in the methylxanthine class of chemical compounds,[3] which also includes the similar compounds theophylline and caffeine.[1] (In caffeine, the only difference is that the NH group of theobromine is an N-CH3 group.) Despite its name, the compound contains no bromine — theobromine is derived from Theobroma, the name of the genus of the cacao tree, (which itself is made up of the Greek roots theo ("God") and brosi ("food"), meaning "food of the gods")[4] with the suffix -ine given to alkaloids and other basic nitrogen-containing compounds.[5]

Theobromine is a water insoluble, crystalline, bitter powder; the colour has been listed as either white or colourless.[6] It has a similar, but lesser, effect to caffeine, making it a lesser homologue. Theobromine is an isomer of theophylline as well as paraxanthine. Theobromine is categorized as a dimethyl xanthine,[7] which means it is a xanthine[8] with two methyl groups.[9]

Theobromine was first discovered in 1841[10] in cacao beans by Russian chemist Alexander Woskresensky.[11] Theobromine was first synthesized from xanthine by Hermann Emil Fischer.[12][13]

Contents

Sources

A chocolate bar and melted chocolate. Chocolate is made from the cacao bean, which is a natural source of theobromine.

Theobromine is the primary alkaloid found in cocoa and chocolate. Cocoa powder can vary in the amount of theobromine, from 2%[14] theobromine to at least 10%[15]. Theobromine can also be found in small amounts in the kola nut (1.0-2.5%), the guarana berry, and the tea plant.[16]

The plant species with the largest amounts of theobromine are:[17]

The mean theobromine concentrations in cocoa and carob products are:[18]

Item Mean theobromine content (mg/g)
Cocoa 20.3
Cocoa cereals 0.695
Chocolate bakery products 1.47
Chocolate toppings 1.95
Cocoa beverages 2.66
Chocolate ice creams 0.621
Chocolate milks 0.226
Carob products 0-0.504

Therapeutic uses

Following its discovery in the late 19th century, theobromine was put to use by 1916, where it was recommended by the publication Principles of Medical Treatment as a treatment for edema (excessive liquid in parts of the body), syphilitic angina attacks, and degenerative angina.[19] The American Journal of Clinical Nutrition notes that theobromine was once used as a treatment for other circulatory problems including arteriosclerosis, certain vascular diseases, angina pectoris, and hypertension.[20]

In modern medicine, theobromine is used as a vasodilator (a blood vessel widener), a diuretic (urination aid), and heart stimulant.[1] In addition, the future use of theobromine in such fields as cancer prevention has been patented.[21]

Theobromine has also been used in birth defect experiments involving mice and rabbits. A decreased fetal weight was noted in rabbits following forced feeding, but not after other administration of theobromine. Birth defects were not seen in rats.[22]

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 10% theobromine, 4% theophylline, and 80% paraxanthine.[23]

In the liver, theobromine is metabolized into methylxanthine and subsequently into methyluric acid.[24] Important enzymes include CYP1A2 and CYP2E1.[25]

Like other methylated xanthine derivatives, theobromine is both a

  1. competitive nonselective phosphodiesterase inhibitor, [26] which raises intracellular cAMP, activates PKA, inhibits TNF-alpha [27][28] and leukotriene [29] synthesis, and reduces inflammation and innate immunity [29] and
  2. nonselective adenosine receptor antagonist [30].

As a phosphodiesterase inhibitor, theobromine helps prevent the phosphodiesterase enzymes from converting the active cAMP to an inactive form.[31] cAMP works as a second messenger in many hormone- and neurotransmitter-controlled metabolic systems, such as the breakdown of glycogen. When the inactivation of cAMP is inhibited by a compound such as theobromine, the effects of the neurotransmitter or hormone that stimulated the production of cAMP are much longer-lived. In general, the net result is a stimulatory effect.[32]

Effects

Humans

A diagram of the bronchus. The loosening of the muscles in the bronchus caused by theobromine helps alleviate the symptoms of asthma.

The amount of theobromine found in chocolate is small enough that chocolate can, in general, be safely consumed by humans. However, theobromine poisoning may result from the chronic or acute consumption of large quantities, especially in the elderly.[33] In extreme cases, emergency room treatment may be required.[34]

While theobromine and caffeine are similar in that they are related alkaloids, theobromine is weaker in both its inhibition of cyclic nucleotide phosphodiesterases and its antagonism of adenosine receptors.[35] Therefore, theobromine has a lesser impact on the human central nervous system than caffeine. However, theobromine stimulates the heart to a greater degree.[citation needed] While theobromine is not as addictive, it has been cited as possibly causing addiction to chocolate.[36] Theobromine has also been identified as one of the compounds contributing to chocolate's reputed role as an aphrodisiac.[37]

As it is a myocardial stimulant as well as a vasodilator, it increases heartbeat, yet it also dilates blood vessels, causing a reduced blood pressure.[38] However, a recent paper published suggested that the decrease in blood pressure may be caused by flavanols.[20] Furthermore, its draining effect allows it to be used to treat cardiac failure, which can be caused by an excessive accumulation of fluid.[38]

A 2004 study published by Imperial College London concluded that theobromine has an antitussive (cough-reducing) effect superior to codeine by suppressing vagus nerve activity.[39] In the study, theobromine significantly increased the capsaicin concentration required to induce coughs when compared with a placebo.[39] In addition, theobromine is helpful in treating asthma, since it relaxes the smooth muscles, including the ones found in the bronchi.[40]

A study conducted in Utah between 1983 and 1986, and published in 1993, showed a possible association between theobromine and an increased risk of suffering from prostate cancer in older men.[41] This association was not found to be linear for aggressive tumors.[41] While the association may be spurious, it is plausible.[41] Prenatal and infant exposure to theobromine appeared possibly associated with hypospadias and testicular cancer in one population study PMID 19440400.

Theobromine can cause sleeplessness, tremors, restlessness, anxiety, as well as contribute to increased production of urine.[40] Additional side effects include loss of appetite, nausea, and vomiting.[42]

Non-human animals

Animals that metabolize theobromine more slowly, such as dogs, can succumb to theobromine poisoning from as little as 50 grams of chocolate for a smaller dog and 400 grams for an average-sized dog. The same risk is reported for cats as well, although cats are less likely to ingest sweet food, having no sweet taste receptors.[43] Birds, again due to their smaller size and more rapid metabolism, are even more susceptible to its toxic effects. 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.[44] Although not usual, the effects of theobromine poisoning, as stated, can become fatal.

Other

Theobromine is known to induce gene mutations in lower eukaryotes and bacteria. At the time of a 1991 report, further updated in 1997, by the IARC, genetic mutations had been found in higher eukaryotic cells, specifically cultured mammalian cells, but the compound was still listed as having inadequate evidence for classification of human carcinogencity.[45]

See also

References

  1. ^ a b c d William Marias Malisoff (1943). Dictionary of Bio-Chemistry and Related Subjects. Philosophical Library. pp. 311, 530, 573. ISBN B0006AQ0NU. 
  2. ^ a b (French) "Theobromine". BIAM. March 29, 2000. http://www.biam2.org/www1/Sub1331.html. Retrieved 2007-03-01. 
  3. ^ Baer, Donald M.; Elsie M. Pinkston (1997). Environment and Behavior. Westview Press. p. 200. 
  4. ^ Bennett, Alan Weinberg; Bonnie K. Bealer (2002). The World of Caffeine: The Science and Culture of the World's Most Popular Drug. Routledge, New York. ISBN 0415927234.  (note: the book incorrectly notes that the name "Theobroma" is derived from Latin)
  5. ^ "-ine." The American Heritage Dictionary of the English Language, Fourth Edition. Houghton Mifflin Company. 2004. ISBN 0395711460. http://dictionary.reference.com/browse/-ine. 
  6. ^ "theobromine". Dictionary.com. http://dictionary.reference.com/search?q=theobromine&db=*. Retrieved 2007-02-22.  For convenience, the direct source of the three definitions used has been cited.
  7. ^ "Theobromine". On-Line Medical Dictionary. http://cancerweb.ncl.ac.uk/cgi-bin/omd?query=theobromine&action=Search+OMD. Retrieved 2007-02-23. 
  8. ^ "Xanthine". On-Line Medical Dictionary. http://cancerweb.ncl.ac.uk/cgi-bin/omd?xanthine. Retrieved 2007-02-23. 
  9. ^ "Dimethyl". On-Line Medical Dictionary. http://cancerweb.ncl.ac.uk/cgi-bin/omd?dimethyl. Retrieved 2007-02-23. 
  10. ^ Plant intoxicants: a classic text on ... - Google Books. Books.google.ru. Retrieved on 2009-11-08.
  11. ^ Woskresensky, A. (1842) "Über das Theobromin," Liebigs Annalen der Chemie und Pharmacie, vol 41, pages 125-127.
  12. ^ Thomas Edward Thorpe (1902). Essays in Historical Chemistry. The MacMillan Company. 
  13. ^ Emil Fischer (1882) "Umwandlung des Xanthin in Theobromin und Caffein," Berichte der deutsche chemischen Gesellschaft, vol. 15, no. 1, pages 453-456. See also: Fischer, E. (1882) "Über Caffein, Theobromin, Xanthin und Guanin," Justus Liebigs Annalen der Chemie, vol. 215, no. 3, pages 253-320.
  14. ^ "Theobromine content of Hershey's confectionery products". The Hershey Company. http://www.hersheys.com/nutrition/theobromine.asp. Retrieved 2008-04-07. 
  15. ^ "AmerMed cocoa extract with 10% theobromine". AmerMed. http://www.amermed.com/cocoa.htm. Retrieved 2008-04-13. 
  16. ^ Sir Ghillean Prance, Mark Nesbitt (2004). The Cultural History of Plants. New York: Routledge. p. 137, 175, 178–180. ISBN 0415927463. 
  17. ^ "Activities of a Specific Chemical Query - Theobromine". United States Department of Agriculture. http://www.ars-grin.gov/cgi-bin/duke/chemical.pl?THEOBROMINE. Retrieved 2007-02-23. 
  18. ^ Craig, Winston J.; Nguyen, Thuy T. (1984). "Caffeine and theobromine levels in cocoa and carob products". Journal of Food Science 49 (1): 302–303. doi:10.1111/j.1365-2621.1984.tb13737.x. http://www.blackwell-synergy.com/doi/abs/10.1111/j.1365-2621.1984.tb13737.x. Retrieved 2008-04-20. "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.". 
  19. ^ George Cheever Shattuck (1916). Principles of medical treatment. W.M. Leonard. p. 15, 39, 41. 
  20. ^ a b Kelly, Caleb J (August 2005). "Effects of theobromine should be considered in future studies". American Journal of Clinical Nutrition 82 (2): 486–8. 
  21. ^ US patent 6693104, "Theobromine with an anti-carcinogenic activity", granted 2004-02-17  
  22. ^ Rambali B, Andel I van, Schenk E, Wolterink G, Werken G van de, Stevenson H, Vleeming W (2002). "[The contribution of cocoa additive to cigarette smoking addiction"] (PDF). RIVM (report 650270002/2002). http://rivm.nl/bibliotheek/rapporten/650270002.pdf. - The National Institute for Public Health and the Environment (Netherlands)
  23. ^ "Caffeine". The Pharmacogenetics and Pharmacogenomics Knowledge Base. http://www.pharmgkb.org/do/serve?objId=464&objCls=DrugProperties. Retrieved 2007-02-22. 
  24. ^ Herbert H. Cornish and A. A. Christman (1957). A Study of the Metabolism of Theobromine, Theophylline, and Caffeine in Man. Department of Biological Chemistry, Medical School, University of Michigan. 
  25. ^ Gates S, Miners JO (March 1999). "Cytochrome P450 isoform selectivity in human hepatic theobromine metabolism". Br J Clin Pharmacol 47 (3): 299–305. doi:10.1046/j.1365-2125.1999.00890.x. PMID 10215755. 
  26. ^ Essayan DM. (2001). "Cyclic nucleotide phosphodiesterases.". J Allergy Clin Immunol. 108 (5): 671–80. doi:10.1067/mai.2001.119555. PMID 11692087. 
  27. ^ Deree J, Martins JO, Melbostad H, Loomis WH, Coimbra R. (2008). "Insights into the regulation of TNF-alpha production in human mononuclear cells: the effects of non-specific phosphodiesterase inhibition.". Clinics (Sao Paulo). 63 (3): 321–8. doi:10.1590/S1807-59322008000300006. PMID 18568240. 
  28. ^ Marques LJ, Zheng L, Poulakis N, Guzman J, Costabel U (February 1999). "Pentoxifylline inhibits TNF-alpha production from human alveolar macrophages". Am. J. Respir. Crit. Care Med. 159 (2): 508–11. PMID 9927365. http://ajrccm.atsjournals.org/cgi/pmidlookup?view=long&pmid=9927365. 
  29. ^ a b Peters-Golden M, Canetti C, Mancuso P, Coffey MJ. (2005). "Leukotrienes: underappreciated mediators of innate immune responses.". J Immunol. 174 (2): 589–94. PMID 15634873. http://www.jimmunol.org/cgi/content/full/174/2/589. 
  30. ^ Daly JW, Jacobson KA, Ukena D. (1987). "Adenosine receptors: development of selective agonists and antagonists.". Prog Clin Biol Res. 230 (1):  :41–63. PMID 3588607. 
  31. ^ * "Phosphodiesterase". On-Line Medical Dictionary. http://cancerweb.ncl.ac.uk/cgi-bin/omd?phosphodiesterase. Retrieved 2007-02-23. 
    "Inhibitor". On-Line Medical Dictionary. http://cancerweb.ncl.ac.uk/cgi-bin/omd?inhibitors. Retrieved 2007-02-23. 
  32. ^ David L. Nelson, Michael M. Cox (2005). Lehninger Principles of Biochemistry. W.H. Freeman and Company. pp. 435–439. ISBN 0716743396. 
  33. ^ See: THEOBROMINE, CASRN: 83-67-0 in the Hazardous Substances Data Bank
  34. ^ Emergency treatment of theobromine poisoning, from the Hazardous Substances Data Bank
  35. ^ Joel Hardman & Lee Limbird, ed (2001). Goodman & Gilman's the pharmacological basis of therapeutics, 10th ed.. New York: McGraw-Hill. p. 745. ISBN 0-07-135469-7. 
  36. ^ William Gervase Clarence-Smith (2000). Cocoa and Chocolate, 1765–1914. London: Routledge. pp. 10, 31. ISBN 0415215765. 
  37. ^ Kenneth Maxwell (1996). A Sexual Odyssey: From Forbidden Fruit to Cybersex. New York: Plenum. pp. 38–40. ISBN 030645405X. 
  38. ^ a b US patent 20050089584, "Methods and compositions for oral delivery of Areca and mate' or theobromine", granted 2005-04-28  
  39. ^ a b Usmani, Omar S.; Belvisi, Maria G.; Patel, Hema J.; Crispino, Natascia; Birrell Mark A.; Korbonits, Márta; Korbonits, Dezső; Barnes, Peter J. (November 17, 2004). "Theobromine inhibits sensory nerve activation and cough". FASEB Journal 19 (2): 231–3. doi:10.1096/fj.04-1990fje. PMID 15548587. http://www.fasebj.org/cgi/reprint/04-1990fjev1. Retrieved 2008-07-04. "The present study demonstrates that theobromine, a methylxanthine derivative present in cocoa, effectively inhibits citric acid-induced cough in guinea-pigs in vivo. Furthermore, in a randomized, double-blind, placebo controlled study in man, theobromine suppresses capsaicin-induced cough with no adverse effects. We also demonstrate that theobromine directly inhibits capsaicin-induced sensory nerve depolarization of guinea-pig and human vagus nerve suggestive of an inhibitory effect on afferent nerve activation.". 
  40. ^ a b Irwin J. Polk (1997). All about Asthma: Stop Suffering and Start Living. New York: Insight Books. p. 100. ISBN 0306455692. 
  41. ^ a b c Slattery, Martha L.; West, Dee W. (1993). "Smoking, alcohol, coffee, tea, caffeine, and theobromine: risk of prostate cancer in Utah (United States)". Cancer Causes Control 4 (6): 559–63. doi:10.1007/BF00052432. PMID 8280834. "Compared with men with very low levels of theobromine intake, older men consuming 11 to 20 and over 20 mg of theobromine per day were at increased risk of prostate cancer (odds ratio-[OR] for all tumors = 2.06, 95 percent confidence interval [CI] = 1.33-3.20, and OR = 1.47, CI = 0.99-2.19, respectively; OR for aggressive tumors -- 1.90, CI = 0.90-3.97, and OR -- 1.74, CI -- 0.91-3.32, respectively)". 
  42. ^ "Theobromine" (in French). BIAM. 2000-03-29. http://www.biam2.org/www1/Sub1331.html. Retrieved 2007-06-10. 
  43. ^ Biello, David (August 16, 2007). "Strange but True: Cats Cannot Taste Sweets". Scientific American. http://www.scientificamerican.com/article.cfm?id=strange-but-true-cats-cannot-taste-sweets. Retrieved July 28, 2009. 
  44. ^ "HEALTH WATCH: How to Avoid a Canine Chocolate Catastrophe!", The News Letter (Belfast, Northern Ireland), 2005-03-01 
  45. ^ International Agency for Research on Cancer (November 17, 1991). "Volume 51: Coffee, Tea, Mate, Methylxanthines and Methylglyoxal - Theobromine" (PDF). IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. WHO. http://monographs.iarc.fr/ENG/Monographs/vol51/volume51.pdf. Retrieved 2006-09-19. 

Further reading

  • Bender, David A.; Arnold E. Bender (1995). A Dictionary of Food and Nutrition. Oxford: Oxford University Press. ISBN 0198609612. 
Antihypertensives: diuretics (C03)
Sulfonamides
(except EA)
Thiazide-likes (primarily DCT)
Potassium-sparing (at CD)
Osmotic diuretics (PT, DL)
VAs (DCT and CD)
Other
mercurial diuretic (Mersalyl) • Theobromine • Cicletanine
Drugs for obstructive airway diseases: asthma/COPD (R03)
Adrenergics, inhalants
other
Glucocorticoids
Anticholinergics/
muscarinic antagonist
Mast cell stabilizers
Xanthines
Eicosanoid inhibition
Combination products
respiratory system navs: anat nose, larynx/lower+thoracic cavity/physio/dev, noncongen/congen/tumors, symptoms+signs/eponymous, proc, meds:R (1/2/3/5/6/7)

Simple English

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Theobromine is a chemical substance, also known as xantheose[1] It is an alkaloid. It occurs in the cacao plant. Chemically, it is very similar to caffeine.[1] Because the cacao plant is used to make chocolate it also occurs in chocolate. Despite its name, there is no bromine in it — theobromine comes from Theobroma, the name of the genus of the cacao tree, (which itself is made up of the Greek roots theo ("God") and brosi ("food"), meaning "food of the gods")[2] with the suffix -ine given to alkaloids and other basic nitrogen-containing compounds.[3]

Theobromine is a water insoluble, crystalline, bitter powder. It colour is listed as either white or colourless.[4] It has a similar, but lesser, effect to caffeine, making it a lesser homologue. Theobromine is an isomer of theophylline as well as paraxanthine. Theobromine is categorized as a dimethyl xanthine,[5] which means it is a xanthine[6] with two methyl groups.[7]

Theobromine was first isolated from the seeds of the cacao tree in 1878[8] and then shortly afterwards was synthesized from xanthine by Hermann Emil Fischer.[9]

References

  1. ↑ 1.0 1.1 William Marias Malisoff (1943). Dictionary of Bio-Chemistry and Related Subjects. Philosophical Library. pp. 311, 530, 573. ISBN B0006AQ0NU. 
  2. ↑ Bennett, Alan Weinberg; Bonnie K. Bealer (2002). The World of Caffeine: The Science and Culture of the World's Most Popular Drug. Routledge, New York. ISBN 0415927234.  (note: the book incorrectly notes that the name "Theobroma" is derived from Latin)
  3. ↑ "-ine." The American Heritage® Dictionary of the English Language, Fourth Edition. Houghton Mifflin Company. 2004. ISBN 0395711460. http://dictionary.reference.com/browse/-ine. 
  4. ↑ "theobromine". Dictionary.com. http://dictionary.reference.com/search?q=theobromine&db=*. Retrieved 2007-02-22.  For convenience, the direct source of the three definitions used has been cited.
  5. ↑ "Theobromine". On-Line Medical Dictionary. http://cancerweb.ncl.ac.uk/cgi-bin/omd?query=theobromine&action=Search+OMD. Retrieved 2007-02-23. 
  6. ↑ "Xanthine". On-Line Medical Dictionary. http://cancerweb.ncl.ac.uk/cgi-bin/omd?xanthine. Retrieved 2007-02-23. 
  7. ↑ "Dimethyl". On-Line Medical Dictionary. http://cancerweb.ncl.ac.uk/cgi-bin/omd?dimethyl. Retrieved 2007-02-23. 
  8. ↑ Walter Sneader (2005). Drug Discovery: A History. John Wiley & Sons. ISBN 0471899801. 
  9. ↑ Thomas Edward Thorpe (1902). Essays in Historical Chemistry. The MacMillan Company. 
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