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Not to be confused with bromine.
Sunnyyaletuth/sandbox/chm275)
Clinical data
Other namesxantheose
diurobromine
3,7-dimethylxanthine
Routes of
administration		Oral
ATC code
Legal status
Legal status
  • In general: uncontrolled
Pharmacokinetic data
MetabolismHepatic demethylation and oxidation
Elimination half-life7.1±0.7 hours
ExcretionRenal (10% unchanged, rest as metabolites)
Identifiers
  • 3,7-dimethyl-1H-purine-2,6-dione
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC7H8N4O2
Molar mass180.164 g/mol g·mol−1
3D model (JSmol)
  • Cn1cnc2c1c(=O)[nH]c(=O)n2C
  • InChI=1S/C7H8N4O2/c1-10-3-8-5-4(10)6(12)9-7(13)11(5)2/h3H,1-2H3,(H,9,12,13) checkY
  • Key:YAPQBXQYLJRXSA-UHFFFAOYSA-N checkY
  (verify)

Theobromine, formerly known as xantheose, is a bitter alkaloid of the cacao plant, with the chemical formula C7H8N4O2.[1] It is found in chocolate, as well as in a number of other foods, including the leaves of the tea plant, and the kola nut. It is classified as a xanthine alkaloid,[2] others of which include theophylline and caffeine.[1] Caffeine differs from the compounds in that it has an extra methyl group (see under Pharmacology section).

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 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), crystalline, bitter powder. Theobromine is white or colourless, but commercial samples can be yellowish.[1] It has an effect similar to, but lesser than, that of 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.[1]

Theobromine was first discovered in 1841[5] in cacao beans by Russian chemist Aleksandr Voskresensky.[6] Synthesis of theobromine from xanthine was first reported in 1882 by Hermann Emil Fischer.[7][8][9]

Sources

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Theobromine is the primary alkaloid found in cocoa and chocolate. Cocoa powder can vary in the amount of theobromine, from 2%[10] theobromine, up to higher levels around 10%. Cocoa butter only contains trace amounts of theobromine. There are usually higher concentrations in dark than in milk chocolate.[11] Theobromine can also be found in trace amounts in the kola nut , the guarana berry, yerba mate (Ilex paraguariensis), Ilex vomitoria, Ilex guayusa, and the tea plant.[12] 28 grams (1 oz) of milk chocolate contains approximately 60 milligrams (1 grain) of theobromine,[13] while the same amount of dark chocolate contains about 200 milligrams (3 grains).[14] Cocoa beans naturally contain approximately 1% theobromine.[15]

Plant species and components with substantial amounts of theobromine are:[16]

The mean theobromine concentrations in cocoa and carob products are:[17]

A chocolate bar and molten chocolate. Chocolate is made from the cocoa bean, which is a natural source of theobromine.
Item Mean theobromine content ratio (10−3)
Cocoa powder 20.3
Cocoa beverages 2.66
Chocolate toppings 1.95
Chocolate bakery products 1.47
Cocoa cereals 0.695
Chocolate ice creams 0.621
Chocolate milks 0.226
Carob products 0.000–0.504

Physical and Chemical Properties

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Theobromine is an odorless and bitter tasting alkaloid with a molecular weight of 180.16 g/mol and pH (saturated solution in water) of 5.5-7. Under standard conditions it is a white to yellow crystalline powder with a melting point of 357 °C.[18] It has a log P value of -0.78, and its density is 1.5g/cm^3 at room temperature.[19]

Biosynthesis

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Theobromine is a purine alkaloid derived from xanthosine, a nucleoside. It is one the three essential methylation step intermediates of the caffeine biosynthesis process (7-methylxanthosine, 7-methylxanthine, and theobromine).[20] The conversion of xanthosine to 7-methylxanthosine proceeds by S-Adenosyl-l-methionine (SAM) dependent xanthosine methyltransferase. Although the mechanism is yet unclear, it is the key enzyme that catalyzes the first methyl transfer in the caffeine biosynthesis pathway to produce the intermediate 7-methylxanthosine.[21] Then, it undergoes a hydrolysis and gives 7-methylxanthine by N-methyl-nucleosidase.[22] The methylation of 7-methylxanthine converts it into theobromine by caffeine synthase.[23] Theobromine is the precursor to caffeine.[24]

Pharmacology

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A diagram featuring 4 skeletal chemical formulas. Top (caffeine) relates to similar compounds paraxanthine, theobromine and theophylline.
Caffeine is metabolized in the liver into three primary metabolites: paraxanthine (84%), theobromine (12%), and theophylline (4%)[citation needed]

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.[25] In the liver, theobromine is metabolized into xanthine and subsequently into methyluric acid.[26] Important enzymes include CYP1A2 and CYP2E1.[27]

"The main mechanism of action for methylxanthines has long been established as an inhibition of adenosine receptors".[1] Its effect as a phosphodiesterase inhibitor[28] is thought to be small.[1]

Pharmacodynamics

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Theobromine, a xanthine derivative like caffeine and the bronchodilator theophylline,[29] is used as a CNS stimulant, mild diuretic, and respiratory stimulant (in neonates with apnea of prematurity).[30]

Mechanism of action

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Theobromine is used as a vasodilator, a diuretic, and heart stimulant.[31] And similar to caffeine, it may be useful in management of fatigue and orthostatic hypotension. It stimulates medullary, vagal, vasomotor, and respiratory centers, promoting bradycardia, vasoconstriction, and increased respiratory rate.[32] This action was previously believed to be due primarily to increased intracellular cyclic 3′,5′-adenosine monophosphate (cyclic AMP) following inhibition of phosphodiesterase, the enzyme that degrades cyclic AMP.[33] It is now thought that xanthines such as caffeine and theobromine act as antagonist at adenosine-receptors within the plasma membrane of virtually every cell. Blockade of the adenosine A1 receptor in the heart leads to the accelerated, pronounced "pounding" of the heart upon caffeine intake.[34]

Effects

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Humans

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It is not currently used as a prescription drug.[1] The amount of theobromine found in chocolate is small enough that chocolate can, in general, be safely consumed by humans. At doses of 0.8–1.5 g/day (50–100 g cocoa), sweating, trembling and severe headaches were noted, with limited mood effects found at 250 mg/day.[35] 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.[36] The potential inhibitory effect of theobromine on phosphodiesterases is seen only at amounts much higher than what people normally would consume in a typical diet including chocolate.[37] In small amounts, is used for medicinal purposes. It increases heart rate, and at the same time, it dilates blood vessels, which lowers the blood pressure.[38] It can also open up airways and is under study as a cough medication.[39] It stimulates urine production and is considered a diuretic.[40] It interacts with the central nervous system (although not as effectively as caffeine). At toxic levels, it provokes acute nausea, vomiting, diarrhea, cardiac arrhythmias, epileptic seizures, internal bleeding and often lethal over-stimulation of the heart, and eventually death.[41]

Animals

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Animals that metabolize theobromine (found in chocolate) more slowly, such as dogs,[42] 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 44-gram (1.55 oz) small milk chocolate bars, for an average-sized dog. The concentration of theobromine in dark chocolates (approximately 10 g/kg (0.16 oz/lb)) is up to 10 times that of milk chocolate (1 to 5 g/kg (0.016 to 0.080 oz/lb)) – 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,[43] although cats are less likely to ingest sweet food, with most cats having no sweet taste receptors.[44] 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.[45] Although not common, the effects of theobromine poisoning can be fatal.

In 2014, four American black bears were found dead at a bait site in New Hampshire. A necropsy and toxicology report performed at the University of New Hampshire in 2015 confirmed they died of heart failure caused by theobromine after they consumed 41 kilograms (90 lb) of chocolate and doughnuts placed at the site as bait. A similar incident killed a black bear cub in Michigan in 2011.[46]


Signs of theobromine poisoning in dogs include vomiting, haematemesis, polydipsia, hyperexcitability, hyperirritability, tachycardia, excessive panting, ataxia, and muscle twitching, progressing to cardiac arrhythmias, seizures, and death. These symptoms can potentially begin within a few hours of ingestion and can persist for up to 72 hours.[47] There is no specific antidote, but treatment protocol usually consists of induced vomiting and administration of activated charcoal, oxygen, benzodiazepines for seizures, antiarrhythmics for heart arrhythmia, and intravenous fluids.[48]

See also

[edit]
  • History of chocolate
  • Theodrenaline
  • Malisoff, William Marias (1943). Dictionary of Bio-Chemistry and Related Subjects. Philosophical Library. pp. 311, 530, 573. ASIN B0006AQ0NU.
  • Daly JW, Jacobson KA, Ukena D (1987). "Adenosine receptors: development of selective agonists and antagonists". Prog Clin Biol Res. 230 (1): 41–63. PMID 3588607.


References

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  1. ^ a b c d e f g Smit, Hendrik Jan (2011). "Theobromine and the Pharmacology of Cocoa". Methylxanthines. Handbook of Experimental Pharmacology. Vol. 200. pp. 201–234. doi:10.1007/978-3-642-13443-2_7. ISBN 978-3-642-13442-5. PMID 20859797.
  2. ^ Baer, Donald M.; Elsie M. Pinkston (1997). Environment and Behavior. Westview Press. p. 200. ISBN 978-0813331591.
  3. ^ 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 978-0-415-92723-9. (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. Houghton Mifflin Company. 2004. ISBN 978-0-395-71146-0.
  5. ^ von Bibra, Ernst; Ott, Jonathan (1995). Plant Intoxicants: A Classic Text on the Use of Mind-Altering Plants. Inner Traditions / Bear & Co. pp. 67–. ISBN 978-0-89281-498-5.
  6. ^ Woskresensky A (1842). "Über das Theobromin". Liebigs Annalen der Chemie und Pharmacie. 41: 125–127. doi:10.1002/jlac.18420410117.
  7. ^ Thorpe, Thomas Edward (1902). Essays in Historical Chemistry. The MacMillan Company.
  8. ^ Fischer, Emil (1882). "Umwandlung des Xanthin in Theobromin und Caffein". Berichte der Deutschen Chemischen Gesellschaft. 15 (1): 453–456. doi:10.1002/cber.18820150194.
  9. ^ Fischer, Emil (1882). "Über Caffein, Theobromin, Xanthin und Guanin". Justus Liebigs Annalen der Chemie. 215 (3): 253–320. doi:10.1002/jlac.18822150302.
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  39. ^ Morice, Alyn H.; McGarvey, Lorcan; Pavord, Ian D.; Higgins, Bernard; Chung, Kian Fan; Birring, Surinder S. (2017-7). "Theobromine for the treatment of persistent cough: a randomised, multicentre, double-blind, placebo-controlled clinical trial". Journal of Thoracic Disease. 9 (7): 1864–1872. doi:10.21037/jtd.2017.06.18. ISSN 2072-1439. PMC 5542984. PMID 28839984. {{cite journal}}: Check date values in: |date= (help)CS1 maint: unflagged free DOI (link)
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[edit]
Wikimedia Commons has media related to Theobromine.

Category:Adenosine receptor antagonists Category:Bitter compounds Category:Components of chocolate Category:IARC Group 3 carcinogens Category:Phosphodiesterase inhibitors Category:Xanthines

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