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Theobromine chemical structure
Theobromine

3,7-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione
IUPAC name
CAS number
83-67-0
ATC code

C03BD01 .

PubChem
5429
DrugBank
[1]
Chemical formula {{{chemical_formula}}}
Molecular weight 180.164 g/mol
Bioavailability
Metabolism Hepatic demethylation and oxidation[1]
Elimination half-life 7.1 +/- 0.7 hours
Excretion Renal (10% unchanged, rest as metabolites)[1]
Pregnancy category
Legal status Uncontrolled substance
Routes of administration Oral

Theobromine, also known as xantheose,[2] is a bitter alkaloid of the cacao plant, found in chocolate, as well as in a number of chocolate-free foods made from theobromine sources including the leaves of the tea plant, the kola or cola nut, and acai berries[citation needed]. It is in the methylxanthine class of chemical compounds,[3] which also includes the similar compounds theophylline and caffeine.[2] (In caffeine, the only difference is that the NH group of theobromine is an N-CH3 group.) Despite its name, the compound contains no brominetheobromine 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]

Theophylline

Theophylline is a stimulant drug obtained by synthetic production. Synthesis is necessary because of its scarcity in nature. Theophylline is synthesized from ethyl 2-cyanoacetate and dimethylurea.

Sources

File:Chocolate02.jpg

Theobromine is the primary alkaloid found in cocoa and chocolate. Cocoa powder such as Hershey's cocoa contains 108 mg (or 2.16%) of theobromine per tablespoon (5g) of powder.[14] However, cocoa powder with more concentrated amounts of theobromine up to at least 10% also exists.[15] Chocolate contains 0.5-2.7% theobromine, although white chocolate contains only trace amounts.[16] Theobromine can also be found in small amounts in the kola nut (1.0-2.5%), the guarana berry, and the tea plant.[17]

The plant species with the largest amounts of theobromine are:[18]

The mean theobromine concentrations in cocoa and carob products are:[19]

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.[20] 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.[21]

In modern medicine, theobromine is used as a vasodilator (a blood vessel widener), a diuretic (urination aid), and heart stimulant.[2] In addition, the future use of theobromine in such fields as cancer prevention has been patented.[22]

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.[23]

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.[24]

In the liver, theobromine is metabolized into methylxanthine and subsequently into methyluric acid.[25] Important enzymes include CYP1A2 and CYP2E1.[26]

Like other methylated xanthine derivatives, theobromine is both a

  1. competitive nonselective phosphodiesterase inhibitor [27] which raises intracellular cAMP, activates PKA, inhibits TNF-alpha [28] [29] and leukotriene [30] synthesis, and reduces inflammation and innate immunity [30] and
  2. nonselective adenosine receptor antagonist [31].

As a phosphodiesterase inhibitor, theobromine helps prevent the phosphodiesterase enzymes from converting the active cAMP to an inactive form.[32] 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 which stimulated the production of cAMP are much longer lived. The net result is generally a stimulatory effect.[33]

Effects

Humans

File:Gray961.png

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.[34] 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.[35] Theobromine has also been identified as one of the compounds contributing to chocolate's reputed role as an aphrodisiac.[36]

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.[37] However, a recent paper published suggested that the decrease in blood pressure may be caused by flavanols.[21] Furthermore, its draining effect allows it to be used to treat cardiac failure, which can be caused by an excessive accumulation of fluid.[37]

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.[38] In the study, theobromine significantly increased the capsaicin concentration required to induce coughs when compared with a placebo.[38] Additionally, theobromine is helpful in treating asthma since it relaxes the smooth muscles, including the ones found in the bronchi.[39]

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.[40] This association was not found to be linear for aggressive tumors.[40] While the association may be spurious, it is plausible.[40]

Theobromine can cause sleeplessness, tremors, restlessness, anxiety, as well as contribute to increased production of urine.[39] Additional side effects include loss of appetite, nausea, and vomiting.[41]

Non-human animals

The amount of theobromine found in chocolate is small enough that it can be safely consumed by humans, but 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.[42] 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.[43] 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 1997 report by the IARC, genetic mutations had not been found in higher eukaryotes, such as humans.[44]

See also

References

  1. 1.0 1.1 (French) Theobromine. BIAM. URL accessed on 2007-03-01.
  2. 2.0 2.1 2.2 William Marias Malisoff (1943). Dictionary of Bio-Chemistry and Related Subjects, 311, 530, 573, Philosophical Library.
  3. Baer, Donald M.; Elsie M. Pinkston (1997). Environment and Behavior, Westview Press.
  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. (note: the book incorrectly notes that the name "Theobroma" is derived from Latin)
  5. "-ine." (2004) The American Heritage Dictionary of the English Language, Fourth Edition, Houghton Mifflin Company.
  6. theobromine. Dictionary.com. URL accessed on 2007-02-22. For convenience, the direct source of the three definitions used has been cited.
  7. Theobromine. On-Line Medical Dictionary. URL accessed on 2007-02-23.
  8. Xanthine. On-Line Medical Dictionary. URL accessed on 2007-02-23.
  9. Dimethyl. On-Line Medical Dictionary. URL accessed on 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. URL accessed on 2008-04-07.
  15. AmerMed cocoa extract with 10% theobromine. AmerMed. URL accessed on 2008-04-13.
  16. America Is Going Sweet on White Chocolate - New York Times
  17. Sir Ghillean Prance, Mark Nesbitt (2004). The Cultural History of Plants, New York: Routledge.
  18. Activities of a Specific Chemical Query - Theobromine. United States Department of Agriculture. URL accessed on 2007-02-23.
  19. Craig, Winston J., Nguyen, Thuy T. (1984). Caffeine and theobromine levels in cocoa and carob products. Journal of Food Science 49 (1): 302–303.
  20. George Cheever Shattuck (1916). Principles of medical treatment, W.M. Leonard.
  21. 21.0 21.1 Kelly, Caleb J (August 2005). Effects of theobromine should be considered in future studies. American Journal of Clinical Nutrition 82 (2): 486–8.
  22. Template:Ref patent
  23. 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]. RIVM (report 650270002/2002).- The National Institute for Public Health and the Environment (Netherlands)
  24. Caffeine. The Pharmacogenetics and Pharmacogenomics Knowledge Base. URL accessed on 2007-02-22.
  25. Herbert H. Cornish and A. A. Christman. "A Study of the Metabolism of Theobromine, Theophylline, and Caffeine in Man". Department of Biological Chemistry, Medical School, University of Michigan.
  26. Gates S, Miners JO (March 1999). Cytochrome P450 isoform selectivity in human hepatic theobromine metabolism. Br J Clin Pharmacol 47 (3): 299–305.
  27. Essayan DM. (2001). Cyclic nucleotide phosphodiesterases.. J Allergy Clin Immunol. 108 (5): 671-80.
  28. 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.
  29. 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.
  30. 30.0 30.1 Peters-Golden M, Canetti C, Mancuso P, Coffey MJ. (2005). Leukotrienes: underappreciated mediators of innate immune responses.. J Immunol. 174 (2): 589-94.
  31. Daly JW, Jacobson KA, Ukena D. (1987). Adenosine receptors: development of selective agonists and antagonists.. Prog Clin Biol Res. 230 (1): :41-63.
  32. * Phosphodiesterase. On-Line Medical Dictionary. URL accessed on 2007-02-23.
    Inhibitor. On-Line Medical Dictionary. URL accessed on 2007-02-23.
  33. David L. Nelson, Michael M. Cox (2005). Lehninger Principles of Biochemistry, 435–439, W.H. Freeman and Company.
  34. (2001) Joel Hardman & Lee Limbird Goodman & Gilman's the pharmacological basis of therapeutics, 10th ed., New York: McGraw-Hill.
  35. William Gervase Clarence-Smith (2000). Cocoa and Chocolate, 1765–1914, 10, 31, London: Routledge.
  36. Kenneth Maxwell (1996). A Sexual Odyssey: From Forbidden Fruit to Cybersex, 38–40, New York: Plenum.
  37. 37.0 37.1 Template:Ref patent
  38. 38.0 38.1 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.
  39. 39.0 39.1 Irwin J. Polk (1997). All about Asthma: Stop Suffering and Start Living, New York: Insight Books.
  40. 40.0 40.1 40.2 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.
  41. Theobromine. BIAM. URL accessed on 2007-06-10.
  42. Biello, David Strange but True: Cats Cannot Taste Sweets. Scientific American. URL accessed on July 28, 2009.
  43. {{{Last}}} ({{{Year}}})
  44. International Agency for Research on Cancer. Volume 51: Coffee, Tea, Mate, Methylxanthines and Methylglyoxal - Theobromine. (PDF) IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. WHO. URL accessed on 2006-09-19.

Further reading

  1. REDIRECT Template:Refbegin
  • Bender, David A.; Arnold E. Bender (1995). A Dictionary of Food and Nutrition, Oxford: Oxford University Press.
  1. redirect Template:Refend


Template:Diuretics Template:Asthma and copd rx

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