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Theobromine

Theobromine
Systematic (IUPAC) name
3,7-dimethyl-1H-purine-2,6-dione
Clinical data
Legal status
  • Uncontrolled substance
Routes Oral
Pharmacokinetic data
Metabolism Hepatic demethylation and oxidation
Half-life 7.1±0.7 hours
Excretion Renal (10% unchanged, rest as metabolites)
Identifiers
CAS number  YesY
ATC code C03 R03
PubChem
DrugBank
ChemSpider  YesY
UNII  YesY
KEGG  YesY
ChEBI  YesY
ChEMBL  YesY
Synonyms xantheose
diurobromine
3,7-dimethylxanthine
Chemical data
Formula C7H8N4O2[1] 
Mol. mass 180.164 g/mol
 YesY   

Theobromine, formerly known as xantheose,[1] is a bitter alkaloid of the cacao plant, with the chemical formula C7H8N4O2. It is 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 classified as a xanthine alkaloid,[2] which also includes the similar compounds theophylline and caffeine.[1] The compounds differ in their degree of methylation.

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 broma ("food"), meaning "food of the gods")[3] with the suffix -ine given to alkaloids and other basic nitrogen-containing compounds.[4]

Theobromine is a slightly water-soluble (330 mg/L[5]), crystalline, bitter powder. Theobromine is white or colourless, but commercial samples can be yellowish.[6] It has a similar, but lesser, effect to caffeine in the human nervous system, making it a lesser homologue. Theobromine is an isomer of theophylline, as well as paraxanthine. Theobromine is categorized as a dimethyl xanthine.[7]

Theobromine was first discovered in 1841[8] in cacao beans by Russian chemist Alexander Voskresensky.[9] Theobromine was first synthesized from xanthine by Hermann Emil Fischer.[10][11]

Contents

  • Sources 1
    • Biosynthesis 1.1
  • Therapeutic uses 2
  • Pharmacology 3
  • Effects 4
    • Humans 4.1
    • Animals 4.2
    • Gene mutation in mammalian cells 4.3
  • See also 5
  • References 6
  • Further reading 7

Sources

A chocolate bar and molten chocolate. Chocolate is made from the cocoa 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%[12] theobromine to at least 10%. There are usually higher concentrations in dark than in milk chocolate.[13] Theobromine can also be found in small amounts in the kola nut (1.0–2.5%), the guarana berry, Ilex paraguariensis (yerba mate), and the tea plant.[14] 1 oz of milk chocolate contains approximately 60 mg of theobromine[15] but 1 oz of dark chocolate contains about 200 mg.[16] Cocoa beans naturally contain approximately 1% theobromine. [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 ratio (10−3)
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 0.000–0.504

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.[20]

Therapeutic uses

In modern medicine, theobromine is used as a vasodilator (a blood vessel widener), a diuretic (urination aid), and heart stimulant.[1]

Theobromine increases urine production. Because of this diuretic effect, and its ability to dilate blood vessels, theobromine has been used to treat high blood pressure.[21] The American Journal of Clinical Nutrition notes that historic use of theobromine as a treatment for other circulatory problems including arteriosclerosis, certain vascular diseases, angina pectoris, and hypertension should be considered in future studies.[22]

Following its discovery in the late 19th century, theobromine was put to use by 1916, when 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.[23]

In the human body, theobromine levels are halved between 6–10 hours after consumption.[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.[24] Possible future uses of theobromine in such fields as cancer prevention have been patented.[25]

Theobromine also shows promise in tooth decay prevention and has been shown in some studies to surpass the more traditional fluoride. Advantages include the ability it safely ingest obviating the do not swallow warnings on standard fluoride toothpaste.[26]

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.[27]

In the liver, theobromine is metabolized into xanthine and subsequently into methyluric acid.[28] Important enzymes include CYP1A2 and CYP2E1.[29]

Like other methylated xanthine derivatives, theobromine is both a:

  1. competitive nonselective phosphodiesterase inhibitor,[30] which raises intracellular cAMP, activates PKA, inhibits TNF-alpha[31][32] and leukotriene[33] synthesis, and reduces inflammation and innate immunity[33] and
  2. nonselective adenosine receptor antagonist.[34]

As a phosphodiesterase inhibitor, theobromine prevents the phosphodiesterase enzymes from converting the active cAMP to an inactive form.[35] 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.[36]

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. Theobromine poisoning may result from the chronic or acute consumption of large quantities, especially in the elderly.[37]

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.[38] Therefore, theobromine has a lesser impact on the human central nervous system than caffeine. Theobromine stimulates the heart to a greater degree.[39] While theobromine is not as addictive, it has been cited as possibly causing addiction to chocolate.[40] Theobromine has also been identified as one of the compounds contributing to chocolate's reputed role as an aphrodisiac.[41]

As it is a myocardial stimulant as well as a vasodilator, it increases heartbeat, and also dilates blood vessels, causing a reduced blood pressure.[42] A 2005 paper published suggested that the decrease in blood pressure may be caused by flavanols.[22] Its draining effect allows it to be used to treat cardiac failure, which leads to and is exacerbated by an excessive accumulation of fluid in the body.[42]

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.[43] In the study, 1000 mg theobromine (equivalent to ~71g dark chocolate) significantly increased the threshold of capsaicin concentration required to induce coughs when compared with a placebo.[43] A drug, called BC1036, is being developed by the private UK company infirst Healthcare and it uses theobromine to treat persistent cough.[44] Theobromine is helpful in treating asthma, since it relaxes the smooth muscles, including the ones found in the bronchi.[45]

A study conducted in Utah between 1983 and 1986, and published in 1993, showed a possible association between theobromine and an increased risk of prostate cancer in older men.[46] This association was not found to be linear for aggressive tumors.[46] The association may be spurious, but is plausible.[46] Prenatal and infant exposure to theobromine appeared possibly associated with hypospadias and testicular cancer in one population study.[47]

As with caffeine, theobromine can cause sleeplessness, tremors, restlessness, anxiety, as well as contribute to increased production of urine.[45] Additional side effects include loss of appetite, nausea, vomiting, and withdrawal headaches.

Animals

Animals that metabolize theobromine (found in chocolate) more slowly, such as dogs [1], can succumb to theobromine poisoning from as little as 50 grams (1.8 oz) of milk chocolate for a smaller dog and 400 grams (14 oz), or around nine 1.55 oz small milk chocolate Hershey bars, for an average-sized dog. It should be observed the concentration of theobromine in dark chocolates (approximately 10 g/kg) is up to 10 times that of milk chocolate (1-5 g/kg) - meaning dark chocolate is far more toxic to dogs per unit weight or volume than milk chocolate.

The same risk is reported for cats as well [2], although cats are less likely to ingest sweet food, with most cats having no sweet taste receptors. 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.[48] Although not usual, the effects of theobromine poisoning, as stated, can become fatal.

The toxicity for birds is not known, but it is typically assumed that it is toxic to birds.[49]

Gene mutation in mammalian cells

Theobromine is known to induce gene mutations in lower eukaryotes and bacteria. In 1991 and 1997, research by the International Agency for Research on Cancer had shown that genetic mutations occurred in higher eukaryotic cells, specifically cultured mammalian cells. But despite this, theobromine was still listed as safe for human consumption due to inadequate evidence of carcinogenicity.[50]

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.  
  2. ^ Baer, Donald M.; Elsie M. Pinkston (1997). Environment and Behavior. Westview Press. p. 200. 
  3. ^ Bennett, Alan Weinberg; Bonnie K. Bealer (2002). The World of Caffeine: The Science and Culture of the World's Most Popular Drug.   (note: the book incorrectly states that the name "theobroma" is derived from Latin)
  4. ^ "-ine."The American Heritage Dictionary of the English Language, Fourth Edition.  
  5. ^ Theobromine in the ChemIDplus database
  6. ^ "theobromine". Dictionary.com. Retrieved 2007-02-22.  For convenience, the direct source of the three definitions used has been cited.
  7. ^ "Theobromine". On-Line Medical Dictionary. Retrieved 2007-02-23. 
  8. ^ Plant intoxicants: a classic text on ... - Google Books. Books.google.ru. Retrieved on 2009-11-08.
  9. ^ Woskresensky A (1842). "Über das Theobromin". Liebigs Annalen der Chemie und Pharmacie 41: 125–127.  
  10. ^ Thomas Edward Thorpe (1902). Essays in Historical Chemistry. The MacMillan Company. 
  11. ^ Fischer Emil (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 215 (3): 253–320.  
  12. ^ "Theobromine content of Hershey's confectionery products". The Hershey Company. Retrieved 2008-04-07. 
  13. ^ "AmerMed cocoa extract with 10% theobromine". AmerMed. Retrieved 2008-04-13. 
  14. ^ Sir Ghillean Prance, Mark Nesbitt (2004). The Cultural History of Plants. New York: Routledge. pp. 137, 175, 178–180.  
  15. ^ "USDA Nutrient database, entries for milk chocolate". Retrieved 2012-12-29. 
  16. ^ "USDA Nutrient database, entries for dark chocolate". Retrieved 2012-11-07. 
  17. ^ http://www.ncbi.nlm.nih.gov/pubmed/1586288
  18. ^ "Activities of a Specific Chemical Query - Theobromine".  
  19. ^ Craig, Winston J.; Nguyen, Thuy T. (1984). "Caffeine and theobromine levels in cocoa and carob products".  
  20. ^ Ashihara, Hiroshi; Yokota, Takao; Crozier, Alan "Biosynthesis and catabolism of purine alkaloids" Advances in Botanical Research 2013, vol. 68, 111-138. http://dx.doi.org/10.1016/B978-0-12-408061-4.00004-3
  21. ^ a b http://chemistry.about.com/od/factsstructures/a/theobromine-chemistry.htm
  22. ^ a b Kelly, Caleb J (August 2005). "Effects of theobromine should be considered in future studies". American Journal of Clinical Nutrition 82 (2): 486–7; author reply 487–8.  
  23. ^ George Cheever Shattuck (1916). Principles of medical treatment. W.M. Leonard. pp. 15, 39, 41. 
  24. ^ 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). - The National Institute for Public Health and the Environment (Netherlands)
  25. ^ US 6693104, "Theobromine with an anti-carcinogenic activity", issued 2004-02-17 
  26. ^ http://www.ncbi.nlm.nih.gov/pubmed/23094271
  27. ^ "Caffeine". The Pharmacogenetics and Pharmacogenomics Knowledge Base. Retrieved 2011-01-08. 
  28. ^ Herbert H. Cornish and A. A. Christman (1957). "A Study of the Metabolism of Theobromine, Theophylline, and Caffeine in Man". Ann Arbor, Michigan: Department of Biological Chemistry, Medical School, University of Michigan. 
  29. ^ Gates S, Miners JO (March 1999). "Cytochrome P450 isoform selectivity in human hepatic theobromine metabolism". Br J Clin Pharmacol 47 (3): 299–305.  
  30. ^ Essayan DM. (2001). "Cyclic nucleotide phosphodiesterases". J Allergy Clin Immunol. 108 (5): 671–80.  
  31. ^ 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 (São Paulo). 63 (3): 321–8.  
  32. ^ 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.  
  33. ^ 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.  
  34. ^ Daly JW, Jacobson KA, Ukena D. (1987). "Adenosine receptors: development of selective agonists and antagonists". Prog Clin Biol Res. 230 (1): 41–63.  
  35. ^ * "Phosphodiesterase". On-Line Medical Dictionary. Retrieved 2007-02-23. 
    "Inhibitor". On-Line Medical Dictionary. Retrieved 2007-02-23. 
  36. ^ David L. Nelson, Michael M. Cox (2005). Lehninger Principles of Biochemistry. W.H. Freeman and Company. pp. 435–439.  
  37. ^ See: THEOBROMINE, CASRN: 83-67-0 in the Hazardous Substances Data Bank
  38. ^ Joel Hardman & Lee Limbird, ed. (2001). Goodman & Gilman's the pharmacological basis of therapeutics, 10th ed. New York: McGraw-Hill. p. 745.  
  39. ^ Howell, L.L., Coffin, V.L., Spealman, R.D. Behavorial and physiological effects of xanthines in nonhuman primates (1997) Psychopharmacology, 129 (1), pp. 1–14.
  40. ^ William Gervase Clarence-Smith (2000). Cocoa and Chocolate, 1765–1914. London: Routledge. pp. 10, 31.  
  41. ^ Kenneth Maxwell (1996). A Sexual Odyssey: From Forbidden Fruit to Cybersex. New York: Plenum. pp. 38–40.  
  42. ^ a b US 20050089584, "Methods and compositions for oral delivery of Areca and mate' or theobromine", issued 2005-04-28 
  43. ^ 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".  
  44. ^ Chocolate cough remedy' in sight"'". BBC News. 2010-12-21. Retrieved 2010-12-21. 
  45. ^ a b Irwin J. Polk (1997). All about Asthma: Stop Suffering and Start Living. New York: Insight Books. p. 100.  
  46. ^ 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.  
  47. ^ Giannandrea F (February 2009). "Correlation analysis of cocoa consumption data with worldwide incidence rates of testicular cancer and hypospadias". Int J Environ Res Public Health 6 (2): 568–78.  
  48. ^ "HEALTH WATCH: How to Avoid a Canine Chocolate Catastrophe!". The News Letter (Belfast, Northern Ireland). 2005-03-01. 
  49. ^ B. Harvey, Toxicoses in Birds.
  50. ^  

Further reading

  • Bender, David A.; Arnold E. Bender (1995). A Dictionary of Food and Nutrition. Oxford: Oxford University Press.  
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