Theobromine 31128 221937024 2008-06-26T19:41:25Z Colin 381149 [[WP:UNDO|Undid]] revision 220889831 by [[Special:Contributions/Tatterfly|Tatterfly]] ([[User talk:Tatterfly|talk]]) Link to epileptic [[seizure]] article. {{Drugbox| |IUPAC_name = 3,7-dihydro-3,7-dimethyl-1H-purine-2,6-dione | image=Theobromin - Theobromine.svg | image2=Theobromine3d.png | 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<ref name="dictbiochem1943"/> | smiles=C[n]1cnc2N(C)C(=O)NC(=O)c12 | synonyms= xantheose<br>diurobromine<br>3,7-dimethylxanthine | molecular_weight = 180.164 g/mol | bioavailability= | metabolism = [[Liver|Hepatic]] [[demethylation]] and [[redox|oxidation]]<ref name="BIAM">{{fr icon}} {{cite web | url = http://www.biam2.org/www1/Sub1331.html | title = Theobromine | accessdate = 2007-03-01 | date = March 29, 2000 | publisher = BIAM}}</ref> | elimination_half-life= 7.1 +/- 0.7 hours | excretion = [[Kidney|Renal]] (10% unchanged, rest as metabolites)<ref name="BIAM"/> | pregnancy_category = | legal_status = Uncontrolled substance | routes_of_administration= [[Oral]] }} '''Theobromine''', also known as '''xantheose''',<ref name="dictbiochem1943"/> is a bitter [[alkaloid]] of the [[cacao]] plant, found in [[chocolate]]. It is in the [[xanthine|methylxanthine]] class of chemical compounds,<ref name="envbeh-p200">{{cite book | title=Environment and Behavior | last = Baer | first = Donald M. | coauthors = Elsie M. Pinkston | year=1997 | publisher=Westview Press | pages=200 }}</ref> which also includes the similar compounds [[theophylline]] and [[caffeine]].<ref name="dictbiochem1943"/> Despite its name, the compound contains no [[bromine]] &mdash; ''theobromine'' is derived from ''Theobroma'', the name of the [[genus]] of the cacao tree, (which itself is made up of the [[Greek (language)|Greek]] roots ''theo'' ("[[God]]") and ''brosi'' ("food"), meaning "food of the gods")<ref name="worldofcaffeine">{{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)</ref> with the suffix ''-ine'' given to alkaloids and other [[Base (chemistry)|basic]] nitrogen-containing compounds.<ref name="dict-ine">"-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 }}</ref> Theobromine is a [[water]] [[solubility|insoluble]], [[crystalline]], bitter powder; the colour has been listed as either [[white]] or [[colourless]].<ref name="theobromine-chemprops">{{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.</ref> It has a similar, but lesser, effect to caffeine, making it a lesser [[homologous series|homologue]]. Theobromine is an [[isomer]] of theophylline as well as [[paraxanthine]]. Theobromine is categorized as a [[methyl|dimethyl]] xanthine,<ref name="omd-theobromine">{{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 }}</ref> which means it is a [[xanthine]]<ref name="omd-xanthine">{{cite web | url=http://cancerweb.ncl.ac.uk/cgi-bin/omd?xanthine | title=Xanthine | publisher=On-Line Medical Dictionary | accessdate=2007-02-23 }}</ref> with two [[methyl]] groups.<ref name="omd-dimethyl">{{cite web | url=http://cancerweb.ncl.ac.uk/cgi-bin/omd?dimethyl | title=Dimethyl | publisher=On-Line Medical Dictionary | accessdate=2007-02-23 }}</ref> Theobromine was first discovered in 1841<ref>[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]</ref> in cacao beans by Russian chemist Alexander Woskresensky. Theobromine was first isolated from the seeds of the cacao tree in 1878<ref name="drugdiscovery">{{cite book | title=Drug Discovery: A History | author=Walter Sneader | isbn=0471899801 | publisher=John Wiley & Sons | date=2005}}</ref> and then shortly afterwards was synthesized from xanthine by [[Hermann Emil Fischer]].<ref name="historicalchemistry">{{cite book | title=Essays in Historical Chemistry | author=Thomas Edward Thorpe | year=1902 | publisher=The MacMillan Company }}</ref> ==Sources== [[Image:Chocolate02.jpg|thumb|left|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 such as Hershey's cocoa contains 108mg of (or 2.16%) theobromine per tablespoon (5g) of powder.<ref name="Hershey_theobromine">{{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}}</ref> However, cocoa powder with more concentrated amounts of theobromine up to at least 10% also exists.<ref name="AmerMed_cocoa">{{cite web |url= http://www.amermed.com/cocoa.htm |title= AmerMed cocoa extract with 10% theobromine |publisher= AmerMed |accessdate=2008-04-13}}</ref> Chocolate contains 0.5-2.7% theobromine, although white chocolate contains only trace amounts.<ref>[http://query.nytimes.com/gst/fullpage.html?res=940DE6DA123CF932A15751C1A96E948260 America Is Going Sweet on White Chocolate - New York Times<!-- Bot generated title -->]</ref> Theobromine can also be found in small amounts in the [[kola nut]] (1.0-2.5%), the [[guarana]] berry, and the [[Camellia sinensis|tea plant]].<ref name="culthistplants">{{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}}</ref> The [[plant]] [[species]] with the largest amounts of theobromine are:<ref name="arsgrin-theobromine">{{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 }}</ref> * ''[[cacao|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:<ref name=Craig1984>{{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 = <small>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.</small>}}</ref> {| class="wikitable" |+ ! Item ! Mean theobromine content (mg/g) |- | Cocoa | 20.3<!--To verify this claim, see Table 1 in the reference--> |- | 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), [[syphilis|syphilitic]] [[Angina pectoris|angina]] attacks, and degenerative angina.<ref name="princimedtreat-1916>{{cite book | title=Principles of medical treatment | author=George Cheever Shattuck | page=15, 39, 41 | year=1916 | publisher=W.M. Leonard }}</ref> ''The American Journal of Clinical Nutrition'' notes that theobromine was once used as a treatment for other circulatory problems including [[arteriosclerosis]], certain [[vascular disease]]s, [[angina pectoris]], and [[hypertension]].<ref name="AJCN">{{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 }}</ref> In modern [[medicine]], theobromine is used as a [[vasodilator]] (a blood vessel widener), an [[diuretic|aid in urinating]], and [[myocardium|heart]] [[stimulant]].<ref name="dictbiochem1943">{{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}}</ref> In addition, the future use of theobromine in such fields as [[cancer]] prevention has been patented.<ref>{{ref patent | number=6693104 | title=Theobromine with an anti-carcinogenic activity | gdate=2004-02-17 | country=US }}</ref> Theobromine has also been used in [[teratology|birth defect]] experiments involving [[mouse|mice]] and [[rabbit]]s. A decreased [[fetus|fetal]] weight was noted in rabbits following [[forced feeding]], but not after other administration of theobromine. Birth defects were not seen in rats.<ref>{{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)</ref> ==Pharmacology== Even without dietary intake, theobromine may occur in the body as it is a product of the human metabolism of [[caffeine]] which is [[metabolism|metabolised]] in the liver into 10% theobromine, 4% [[theophylline]], and 80% [[paraxanthine]].<ref name="pharmgkb">{{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 }}</ref> In the liver, theobromine is metabolized into [[methylxanthine]] and subsequently into [[methyluric acid]].<ref>{{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 }}</ref> Important enzymes include [[CYP1A2]] and [[CYP2E1]].<ref>{{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 <!--Retrieved from CrossRef by DOI bot-->}}</ref> As a methylated xanthine, theobromine is a potent [[Cyclic adenosine monophosphate]] (cAMP) [[phosphodiesterase inhibitor]];<ref name="omd-xanthine"/> this means that it helps prevent the enzyme phosphodiesterase from converting the active cAMP to an inactive form.<ref name="omd-pdaseinhibitor">* {{cite web | url=http://cancerweb.ncl.ac.uk/cgi-bin/omd?phosphodiesterase | title=Phosphodiesterase | publisher=On-Line Medical Dictionary | accessdate=2007-02-23 }}<br/> {{cite web | url=http://cancerweb.ncl.ac.uk/cgi-bin/omd?inhibitors | title=Inhibitor | publisher=On-Line Medical Dictionary | accessdate=2007-02-23 }}</ref> 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.<ref name="lehningerbiochem">{{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 }}</ref> ==Effects== ===Humans=== [[Image:Gray961.png|thumb|right|A diagram of the bronchus. The loosening of the muscles in the bronchus caused by theobromine helps alleviate the symptoms of asthma.]] 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 [[antagonist|antagonism]] of [[adenosine receptors]]<ref name="therapeutics">{{cite 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}}</ref>. 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.<ref name="cocoachocolate">{{cite book | author=William Gervase Clarence-Smith| title=Cocoa and Chocolate, 1765-1914 | year=2000 | publisher=Routledge | location=London | pages=10, 31 | isbn = 0415215765 }}</ref> Theobromine has also been identified as one of the compounds contributing to [[Chocolate#Aphrodisiac|chocolate's reputed role as an aphrodisiac]].<ref name="sexualodyssey">{{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 }}</ref> 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 name="arecapatent">{{ref patent | country=US | number=20050089584 | title=Methods and compositions for oral delivery of Areca and mate' or theobromine | gdate=2005-04-28 }}</ref> However, a recent paper published suggested that the decrease in blood pressure may be caused by flavanols.<ref name="AJCN"/> Furthermore, its draining effect allows it to be used to treat [[cardiac failure]], which can be caused by an excessive accumulation of fluid.<ref name="arecapatent"/> A 2004 study published by [[Imperial College London]] concluded that theobromine has an [[cough medicine|antitussive]] (cough-reducing) effect superior to [[codeine]] by suppressing [[vagus nerve]] activity.<ref name=PMID_15548587>{{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 = [[Federation of American Societies for Experimental Biology|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 = <small>The present study demonstrates that theobromine, a methylxanthine derivative present in cocoa, effectively inhibits [[citric acid]] induced cough in [[guinea pig|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.</small>}}</ref> In the study, theobromine significantly increased the [[capsaicin]] concentration required to induce coughs when compared with a placebo.<ref name=PMID_15548587/> Additionally, theobromine is helpful in treating [[asthma]] since it relaxes the [[smooth muscle]]s, including the ones found in the [[bronchus|bronchi]].<ref name="asthma">{{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 }}</ref> 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.<ref name=PMID_8280834>{{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 = <small>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)</small> | doi = 10.1007/BF00052432 <!--Retrieved from CrossRef by DOI bot-->}}</ref> This association was not found to be linear for aggressive tumors.<ref name=PMID_8280834/> While the association may be spurious, it is plausible.<ref name=PMID_8280834/> Theobromine can cause sleeplessness, tremors, restlessness, anxiety, as well as contribute to [[diuresis|increased production of urine]].<ref name="asthma"/> Additional side effects include [[anorexia (symptom)|loss of appetite]], [[nausea]], and [[vomiting]].<ref name="biam">{{cite web | url=http://www.biam2.org/www1/Sub1331.html | title=Theobromine | publisher=BIAM | language=French | date=2000-03-29 | accessdate=2007-06-10 }}</ref> ===Animals=== The amount of theobromine found in chocolate is small enough that it can be safely consumed by [[human]]s, but animals that [[metabolize]] theobromine more slowly, such as [[dog]]s, 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 [[cat]]s 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 [[epilepsy|epileptic]]-like [[seizure]]s and death. If caught early on, theobromine poisoning is treatable.<ref name="healthwatchcanines">{{harvard reference | title=HEALTH WATCH: How to Avoid a Canine Chocolate Catastrophe! | newspaper=The News Letter | location=Belfast, Northern Ireland | date=2005-03-01}}</ref> Although not usual, the effects of theobromine poisoning can become fatal. ===Other=== Theobromine is known to induce [[gene]] [[mutation]]s in lower [[eukaryote]]s and [[bacterium|bacteria]]. At the time of a [[1997]] report by the [[International Agency for Research on Cancer|IARC]], genetic mutations had not been found in higher eukaryotes, such as humans.<ref>{{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=[[World Health Organization|WHO]] | date=November 17, 1991 | accessdate=2006-09-19}}</ref> ==See also== * [[History of chocolate]] ==References== {{Reflist|2}} ==Further reading== {{sourcesstart}} * {{cite book | last = Bender | first = David A. | coauthors = Arnold E. Bender | title=A Dictionary of Food and Nutrition | year=1995 | publisher=Oxford University Press | location=Oxford | isbn = 0198609612 }} {{sourcesend}} {{Antihypertensives and diuretics}} {{Asthma and copd rx}} [[Category:Chocolate]] [[Category:IARC Group 3 carcinogens]] [[Category:Xanthines]] [[Category:Bitter compounds]] [[bg:Теобромин]] [[ca:Teobromina]] [[da:Theobromin]] [[de:Theobromin]] [[es:Teobromina]] [[fr:Théobromine]] [[hr:Teobromin]] [[it:Teobromina]] [[he:תאוברומין]] [[hu:Teobromin]] [[nl:Theobromine]] [[ja:テオブロミン]] [[no:Teobromin]] [[nn:Teobromin]] [[pl:Teobromina]] [[pt:Teobromina]] [[ro:Teobromină]] [[ru:Теобромин]] [[simple:Theobromine]] [[sk:Teobromín]] [[fi:Teobromiini]] [[sv:Teobromin]] [[uk:Теобромін]] [[zh:可可碱]]