Theobromine

Drugbox
IUPAC_name = 3,7-dihydro-3,7-dimethyl-1H-purine-2,6-dione

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CAS_number=83-67-0
ATC_prefix=C03
ATC_suffix=BD01
ATC_supplemental=ATC|R03|DA07
PubChem=5429
DrugBank=
C=7 | H=8 | N=4 | O=2
smiles=C [n] 1cnc2N(C)C(=O)NC(=O)c12
synonyms= xantheose
diurobromine
3,7-dimethylxanthine
molecular_weight = 180.164 g/mol
bioavailability=
metabolism = Hepatic demethylation and oxidationfr icon cite web | url = http://www.biam2.org/www1/Sub1331.html | title = Theobromine | accessdate = 2007-03-01 | date = March 29, 2000 | publisher = BIAM]
elimination_half-life= 7.1 +/- 0.7 hours
excretion = Renal (10% unchanged, rest as metabolites)
pregnancy_category =
legal_status = Uncontrolled substance
routes_of_administration= Oral

Theobromine, also known as xantheose, is a bitter alkaloid of the cacao plant, found in chocolate. It is in the methylxanthine class of chemical compounds,cite book | title=Environment and Behavior | last = Baer | first = Donald M. | coauthors = Elsie M. Pinkston | year=1997 | publisher=Westview Press | pages=200 ] which also includes the similar compounds theophylline and caffeine. 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")cite book | last = Bennett | first = Alan Weinberg | coauthors = Bonnie K. Bealer | title = The World of Caffeine: The Science and Culture of the World's Most Popular Drug | publisher = Routledge, New York | date = 2002 | isbn = 0415927234 (note: the book incorrectly notes that the name "Theobroma" is derived from Latin)] with the suffix "-ine" given to alkaloids and other basic nitrogen-containing compounds."-ine."cite book | title = The American Heritage® Dictionary of the English Language, Fourth Edition | publisher = Houghton Mifflin Company | date = 2004 | url = http://dictionary.reference.com/browse/-ine | isbn = 0395711460 ]

Theobromine is a water insoluble, crystalline, bitter powder; the colour has been listed as either white or colourless.cite web | url=http://dictionary.reference.com/search?q=theobromine&db=* | title=theobromine | publisher=Dictionary.com | accessdate=2007-02-22 For convenience, the direct source of the three definitions used has been cited.] 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,cite web | url=http://cancerweb.ncl.ac.uk/cgi-bin/omd?query=theobromine&action=Search+OMD | title=Theobromine | publisher=On-Line Medical Dictionary | accessdate=2007-02-23 ] which means it is a xanthinecite web | url=http://cancerweb.ncl.ac.uk/cgi-bin/omd?xanthine | title=Xanthine | publisher=On-Line Medical Dictionary | accessdate=2007-02-23 ] with two methyl groups.cite web | url=http://cancerweb.ncl.ac.uk/cgi-bin/omd?dimethyl | title=Dimethyl | publisher=On-Line Medical Dictionary | accessdate=2007-02-23 ]

Theobromine was first discovered in 1841 [ [http://books.google.ru/books?id=EWqhC4djXSQC&pg=PA67&lpg=PA67&dq=Theobromine+1841&source=web&ots=PZISTwSSiB&sig=wlF1zok-GMU1xRakPPmBi_7Qagw&hl=en&sa=X&oi=book_result&resnum=1&ct=result#PPA67,M1] ] in cacao beans by Russian chemist Alexander Woskresensky. Theobromine was first isolated from the seeds of the cacao tree in 1878cite book | title=Drug Discovery: A History | author=Walter Sneader | isbn=0471899801 | publisher=John Wiley & Sons | date=2005] and then shortly afterwards was synthesized from xanthine by Hermann Emil Fischer.cite book | title=Essays in Historical Chemistry | author=Thomas Edward Thorpe | year=1902 | publisher=The MacMillan Company ]

ources

Theobromine is the primary alkaloid found in cocoa and chocolate. Cocoa powder such as Hershey's cocoa contains 108mg of (or 2.16%) theobromine per tablespoon (5g) of powder.cite web |url= http://www.hersheys.com/nutrition/theobromine.asp |title= Theobromine content of Hershey's confectionery products |publisher= The Hershey Company |accessdate=2008-04-07] However, cocoa powder with more concentrated amounts of theobromine up to at least 10% also exists.cite web |url= http://www.amermed.com/cocoa.htm |title= AmerMed cocoa extract with 10% theobromine |publisher= AmerMed |accessdate=2008-04-13] Chocolate contains 0.5-2.7% theobromine, although white chocolate contains only trace amounts. [ [http://query.nytimes.com/gst/fullpage.html?res=940DE6DA123CF932A15751C1A96E948260 America Is Going Sweet on White Chocolate - New York Times ] ] Theobromine can also be found in small amounts in the kola nut (1.0-2.5%), the guarana berry, and the tea plant.cite book | author=Sir Ghillean Prance, Mark Nesbitt | title=The Cultural History of Plants | publisher=Routledge | year=2004 | location=New York | page=137, 175, 178–180 | isbn = 0415927463]

The plant species with the largest amounts of theobromine are:cite web | url=http://www.ars-grin.gov/cgi-bin/duke/chemical.pl?THEOBROMINE | title=Activities of a Specific Chemical Query - Theobromine | publisher=United States Department of Agriculture | accessdate=2007-02-23 ]

* "Theobroma cacao"
* "Theobroma bicolor"
* "Yerba mate"
* "Camellia sinensis"
* "Cola acuminata"
* "Theobroma angustifolium"
* "Guarana"
* "Coffea arabica"

The mean theobromine concentrations in cocoa and carob products are:cite journal| author = Craig, Winston J.| coauthors = Nguyen, Thuy T.| year = 1984| title = Caffeine and theobromine levels in cocoa and carob products| journal = Journal of Food Science| volume = 49| issue = 1| pages = 302–303| doi = 10.1111/j.1365-2621.1984.tb13737.x| url = http://www.blackwell-synergy.com/doi/abs/10.1111/j.1365-2621.1984.tb13737.x| accessdate = 2008-04-20
quote = 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.]

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.arteriosclerosis, certain vascular diseases, angina pectoris, and hypertension.cite journal | title=Effects of theobromine should be considered in future studies | last=Kelly | first=Caleb J | year=2005 | month=August | journal=American Journal of Clinical Nutrition | volume=82 | issue=2 | pages=486–8 ]

In modern medicine, theobromine is used as a vasodilator (a blood vessel widener), a diuretic (urination aid), and heart stimulant.cite book | title=Dictionary of Bio-Chemistry and Related Subjects | author=William Marias Malisoff | year=1943 | publisher=Philosophical Library | pages=311, 530, 573 | isbn = B0006AQ0NU] In addition, the future use of theobromine in such fields as cancer prevention has been patented. [ref patent | number=6693104 | title=Theobromine with an anti-carcinogenic activity | gdate=2004-02-17 | country=US ]

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. [cite journal | author=Rambali B, Andel I van, Schenk E, Wolterink G, Werken G van de, Stevenson H, Vleeming W | title= [The contribution of cocoa additive to cigarette smoking addiction] | journal=RIVM | year=2002 | url=http://rivm.nl/bibliotheek/rapporten/650270002.pdf | format=PDF | issue=report 650270002/2002- The National Institute for Public Health and the Environment (Netherlands)]

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.cite web | title = Caffeine | publisher = The Pharmacogenetics and Pharmacogenomics Knowledge Base | url = http://www.pharmgkb.org/do/serve?objId=464&objCls=DrugProperties | accessdate = 2007-02-22 ]

In the liver, theobromine is metabolized into methylxanthine and subsequently into methyluric acid. [cite paper | title=A Study of the Metabolism of Theobromine, Theophylline, and Caffeine in Man | author=Herbert H. Cornish and A. A. Christman | date=1957 | publisher=Department of Biological Chemistry, Medical School, University of Michigan | city=Ann Arbor, Michigan ] Important enzymes include CYP1A2 and CYP2E1. [cite journal| journal=Br J Clin Pharmacol| year=1999| month=March| volume=47| issue=3| pages=299–305| author=Gates S, Miners JO| title=Cytochrome P450 isoform selectivity in human hepatic theobromine metabolism| pmid=10215755 | doi = 10.1046/j.1365-2125.1999.00890.x ]

As a methylated xanthine, theobromine is a potent Cyclic adenosine monophosphate (cAMP) phosphodiesterase inhibitor; this means that it helps prevent the enzyme phosphodiesterase from converting the active cAMP to an inactive form.* cite web | url=http://cancerweb.ncl.ac.uk/cgi-bin/omd?phosphodiesterase | title=Phosphodiesterase | publisher=On-Line Medical Dictionary | accessdate=2007-02-23 cite web | url=http://cancerweb.ncl.ac.uk/cgi-bin/omd?inhibitors | title=Inhibitor | publisher=On-Line Medical Dictionary | accessdate=2007-02-23 ] 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.cite book | title=Lehninger Principles of Biochemistry | author=David L. Nelson, Michael M. Cox | year=2005 | publisher=W.H. Freeman and Company | pages=435–439 | isbn = 0716743396 ]

Effects

Humans

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 receptorscite book | editor=Joel Hardman & Lee Limbird | title=Goodman & Gilman's the pharmacological basis of therapeutics, 10th ed. | publisher=McGraw-Hill | location=New York | year=2001 | page=745 | isbn=0-07-135469-7] . Therefore, theobromine has a lesser impact on the human central nervous system than caffeine. However, theobromine stimulates the heart to a greater degree.Fact|date=May 2008 While theobromine is not as addictive, it has been cited as possibly causing addiction to chocolate.cite book | author=William Gervase Clarence-Smith| title=Cocoa and Chocolate, 1765-1914 | year=2000 | publisher=Routledge | location=London | pages=10, 31 | isbn = 0415215765 ] Theobromine has also been identified as one of the compounds contributing to chocolate's reputed role as an aphrodisiac.cite book | author=Kenneth Maxwell | title=A Sexual Odyssey: From Forbidden Fruit to Cybersex | publisher=Plenum | location=New York | year=1996 | pages=38-40 | isbn = 030645405X ]

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.ref patent | country=US | number=20050089584 | title=Methods and compositions for oral delivery of Areca and mate' or theobromine | gdate=2005-04-28 ] However, a recent paper published suggested that the decrease in blood pressure may be caused by flavanols. Furthermore, its draining effect allows it to be used to treat cardiac failure, which can be caused by an excessive accumulation of fluid.

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.cite journal | author = Usmani, Omar S.; Belvisi, Maria G.; Patel, Hema J.; Crispino, Natascia; Birrell Mark A.; Korbonits, Márta; Korbonits, Dezső; Barnes, Peter J. | title = Theobromine inhibits sensory nerve activation and cough | journal = FASEB Journal | volume = 19 | issue = 2 | pages = 231–3 | year = 2004 | pmid = 15548587 | url = http://www.fasebj.org/cgi/reprint/04-1990fjev1 | doi = 10.1096/fj.04-1990fje | accessdate = 2008-07-04 | date = November 17, 2004 | quote = 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.] In the study, theobromine significantly increased the capsaicin concentration required to induce coughs when compared with a placebo. Additionally, theobromine is helpful in treating asthma since it relaxes the smooth muscles, including the ones found in the bronchi.cite book | author=Irwin J. Polk | title=All about Asthma: Stop Suffering and Start Living | year=1997 | location=New York | publisher=Insight Books | pages=100 | isbn = 0306455692 ]

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.cite journal | author = Slattery, Martha L.; West, Dee W. | title = Smoking, alcohol, coffee, tea, caffeine, and theobromine: risk of prostate cancer in Utah (United States) | journal = Cancer Causes Control | volume = 4 | issue = 6 | pages = 559–63 | year = 1993 | pmid = 8280834 | quote = 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) | doi = 10.1007/BF00052432 ] This association was not found to be linear for aggressive tumors. While the association may be spurious, it is plausible.

Theobromine can cause sleeplessness, tremors, restlessness, anxiety, as well as contribute to increased production of urine. Additional side effects include loss of appetite, nausea, and vomiting.cite web | url=http://www.biam2.org/www1/Sub1331.html | title=Theobromine | publisher=BIAM | language=French | date=2000-03-29 | accessdate=2007-06-10 ]

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. 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.harvard reference | title=HEALTH WATCH: How to Avoid a Canine Chocolate Catastrophe! | newspaper=The News Letter | location=Belfast, Northern Ireland | date=2005-03-01] Although not usual, the effects of theobromine poisoning 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. [cite web | author=International Agency for Research on Cancer | title=Volume 51: Coffee, Tea, Mate, Methylxanthines and Methylglyoxal - Theobromine | url=http://monographs.iarc.fr/ENG/Monographs/vol51/volume51.pdf | format=PDF | work=IARC Monographs on the Evaluation of Carcinogenic Risks to Humans | publisher=WHO | date=November 17, 1991 | accessdate=2006-09-19]

ee also

* History of chocolate
* Theobromine poisoning

References

Further reading

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