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Theobromine



Theobromine
Systematic (IUPAC) name
3,7-dihydro-3,7-dimethyl-1H-purine-2,6-dione
Identifiers
CAS number	83-67-0
ATC code	C03BD01 R03DA07
PubChem	5429
Chemical data
Formula	C₇H₈N₄O_2^[1]
Mol. mass	180.164 g/mol
SMILES	search in eMolecules, PubChem
Synonyms	xantheose diurobromine 3,7-dimethylxanthine
Pharmacokinetic data
Bioavailability	?
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

Theobromine, also known as xantheose,^[1] is a bitter alkaloid of the cacao plant, and is therefore found in chocolate. It is in the methylxanthine class of chemical compounds,^[3] which also includes the similar compounds theophylline and caffeine.^[1] 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 isolated from the seeds of the cacao tree in 1878^[10] and then shortly afterwards was synthesized from xanthine by Hermann Emil Fischer.^[11]

Additional recommended knowledge

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Sources

Theobromine is the primary alkaloid found in cocoa and chocolate; chocolate contains 0.5-2.7% theobromine (though white chocolate contains only trace amounts^[12]). Theobromine can also be found in small amounts in the kola nut (1.0-2.5%), the guarana berry, and the tea plant.^[13]

In the human liver, caffeine is metabolised by enzymes into 10% theobromine, 4% theophylline, and 80% paraxanthine.^[14]

The plant species with the largest amounts of theobromine are:^[15]

Theobroma cacao
Theobroma bicolor
Ilex paraguariensis
Camellia sinensis
Cola acuminata
Theobroma angustifolium
Paullinia cupana
Coffea arabica

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.^[16] 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.^[17]

In modern medicine, theobromine is used as a vasodilator (a blood vessel widener), an aid in urinating, and heart stimulant.^[1] In addition, the future use of theobromine in such fields as cancer prevention has been patented.^[18]

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.^[19]

Pharmacology

In the human liver, theobromine is metabolized into methylxanthine and subsequently into methyluric acid.^[20]

As a methylated xanthine, theobromine is a potent Cyclic adenosine monophosphate (cAMP) phosphodiesterase inhibitor;^[8] this means that it helps prevent the enzyme phosphodiesterase from converting the active cAMP to an inactive form.^[21] Cyclic Adenosine Monophosphate 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.^[22]

Effects

Humans

Further reading: Chocolate as an aphrodisiac

While theobromine and caffeine are similar in that they are related alkaloids, theobromine has a lesser impact on the human central nervous system and it stimulates the heart to a greater degree.^[23] While theobromine is not as addictive, it has been cited as possibly causing addiction to chocolate.^[24] A Sexual Odyssey: From Forbidden Fruit to Cybersex discusses how chocolate's alleged aphrodisiac effects may be caused by a number of factors. These include the stimulative effects of theobromine, pleasure induced by the hypothalamus as an effect of chocolate's sweet and fatty nature, or how chocolate affects the levels of serotonin. While serotonin has a pleasurable effect, in high concentrations it can be converted to melatonin which in large amounts reduces sexual drive.^[23]

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.^[25] However, a recent paper published suggested that the decrease in blood pressure may be caused by flavanols.^[17] Furthermore, its draining effect allows it to be used to treat cardiac failure, which can be caused by an excessive accumulation of fluid.^[25]

A 2005 study published by Imperial College London concluded that theobromine has an antitussive (cough-reducing) effect superior to codeine by suppressing vagus nerve activity.^[26] Additionally, theobromine is helpful in treating asthma since it relaxes the smooth muscles, including the ones found in the bronchi.^[27]

There is a possible association between theobromine and an increased risk of suffering from prostate cancer.^[28]

Theobromine can cause sleeplessness, tremors, restlessness, anxiety, as well as contribute to increased production of urine.^[27] Additional side effects include loss of appetite, nausea, and vomiting.^[29]

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. 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.^[30]

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.^[31]

References

^ ^a ^b ^c ^d William Marias Malisoff (1943). Dictionary of Bio-Chemistry and Related Subjects. Philosophical Library, 311, 530, 573. ISBN B0006AQ0NU.
^ ^a ^b (French) Theobromine. BIAM (March 29, 2000). Retrieved on 2007-03-01.
^ Baer, Donald M.; Elsie M. Pinkston (1997). Environment and Behavior. Westview Press, 200.
^ 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)
^ "-ine." (2004) The American Heritage® Dictionary of the English Language, Fourth Edition. Houghton Mifflin Company. ISBN 0395711460.
^ theobromine. Dictionary.com. Retrieved on 2007-02-22. For convenience, the direct source of the three definitions used has been cited.
^ Theobromine. On-Line Medical Dictionary. Retrieved on 2007-02-23.
^ ^a ^b Xanthine. On-Line Medical Dictionary. Retrieved on 2007-02-23.
^ Dimethyl. On-Line Medical Dictionary. Retrieved on 2007-02-23.
^ Walter Sneader (2005). Drug Discovery: A History. John Wiley & Sons. ISBN 0471899801.
^ Thomas Edward Thorpe (1902). Essays in Historical Chemistry. The MacMillan Company.
^ http://query.nytimes.com/gst/fullpage.html?res=940DE6DA123CF932A15751C1A96E948260
^ Sir Ghillean Prance, Mark Nesbitt (2004). The Cultural History of Plants. New York: Routledge, 137, 175, 178–180. ISBN 0415927463.
^ Caffeine. The Pharmacogenetics and Pharmacogenomics Knowledge Base. Retrieved on 2007-02-22.
^ Activities of a Specific Chemical Query - Theobromine. United States Department of Agriculture. Retrieved on 2007-02-23.
^ George Cheever Shattuck (1916). Principles of medical treatment. W.M. Leonard, 15, 39, 41.
^ ^a ^b Kelly, Caleb J (August 2005). "Effects of theobromine should be considered in future studies". American Journal of Clinical Nutrition 82 (2).
^ US patent 6693104, "Theobromine with an anti-carcinogenic activity", granted 2004-02-17
^ 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)
^ 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.
^ * Phosphodiesterase. On-Line Medical Dictionary. Retrieved on 2007-02-23.
- Inhibitor. On-Line Medical Dictionary. Retrieved on 2007-02-23.
^ David L. Nelson, Michael M. Cox (2005). Lehninger Principles of Biochemistry. W.H. Freeman and Company, 435–439. ISBN 0716743396.
^ ^a ^b Kenneth Maxwell (1996). A Sexual Odyssey: From Forbidden Fruit to Cybersex. New York: Plenum, 38-40. ISBN 030645405X.
^ William Gervase Clarence-Smith (2000). Cocoa and Chocolate, 1765-1914. London: Routledge, 10, 31. ISBN 0415215765.
^ ^a ^b US patent 20050089584, "Methods and compositions for oral delivery of Areca and mate' or theobromine", granted 2005-04-28
^ Usmani O; Belvisi M, Patel H, Crispino N, Birrell M, Korbonits M, Korbonits D, Barnes P (2005). "Theobromine inhibits sensory nerve activation and cough.". FASEB J 19 (2): 231-3. PMID 15548587.
^ ^a ^b Irwin J. Polk (1997). All about Asthma: Stop Suffering and Start Living. New York: Insight Books, 100. ISBN 0306455692.
^ Slattery M, West D (1993). "Smoking, alcohol, coffee, tea, caffeine, and theobromine: risk of prostate cancer in Utah (United States).". Cancer Causes Control 4 (6): 559-63. PMID 8280834.
^ Theobromine (French). BIAM (2000-03-29). Retrieved on 2007-06-10.
^ " ", The News Letter, 2005-03-01
^ 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. Retrieved on 2006-09-19.