Theobromine

Theobromine, also known as xantheose, is an alkaloid. It is white or colourless solid, but commercial samples can appear yellowish.[4] or white solid, it is the principal alkaloid of Theobroma cacao (cacao plant).[5] Theobromine is a slightly water-soluble (330 mg/L) with a bitter taste.[4] In industry, theobromine is used as an additive and precursor to some cosmetics.[5] 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.

Theobromine
Clinical data
Other namesxantheose
diurobromine
3,7-dimethylxanthine
3,7-dihydro-3,7-dimethyl-1H-purine-2,6-dione
Routes of
administration		Oral
ATC code
Legal status
Legal status
  • In general: uncontrolled
Pharmacokinetic data
MetabolismHepatic demethylation and oxidation
Elimination half-life6–8 hours[1][2]
ExcretionRenal (10% unchanged, rest as metabolites)
Identifiers
IUPAC name
  • 3,7-dimethyl-1H-purine-2,6-dione
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.001.359
Chemical and physical data
FormulaC7H8N4O2
Molar mass180.167 g·mol−1
3D model (JSmol)
SMILES
  • Cn1cnc2c1c(=O)[nH]c(=O)n2C
InChI
  • 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) Y
  • Key:YAPQBXQYLJRXSA-UHFFFAOYSA-N Y
  (verify)
Theobromine
Identifiers
ECHA InfoCard 100.001.359
Properties
Appearance white solid
Density 1.524 g/cm3[3]
Melting point 351 °C (664 °F; 624 K)
Solubility in water
 330 mg/L)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references

Structure

Theobromine is a flat molecule,[3] a derivative of purine. It is also classified as a dimethyl xanthine.[4]),[6] Related compounds include theophylline and caffeine, as well as paraxanthine.[4] Caffeine differs from these compounds in that it has an extra methyl group (see under Pharmacology section).

History

Theobromine was first discovered in 1841[7] in cacao beans by Russian chemist Aleksandr Voskresensky.[8] Synthesis of theobromine from xanthine was first reported in 1882 by Hermann Emil Fischer.[9][10][11]

Etymology

Theobromine is derived from Theobroma, the name of the genus of the cacao tree, with the suffix -ine given to alkaloids and other basic nitrogen-containing compounds.[12] That name in turn is made up of the Greek roots theo ("god") and broma ("food"), meaning "food of the gods".[13]

Despite its name, the compound contains no bromine.

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 butter only contains trace amounts of theobromine. There are usually higher concentrations in dark than in milk chocolate.[14]

There are approximately 60 milligrams (1 grain) of theobromine in 28 grams (1 oz) of milk chocolate,[15] while the same amount of dark chocolate contains about 200 milligrams (3 grains).[16] Cocoa beans naturally contain approximately 1% theobromine.[17]

Plant species and components with substantial amounts of theobromine are:[18]

  • Theobroma cacao – seed and seed coat
  • Theobroma bicolor – seed coat
  • Ilex paraguariensis – leaf
  • Camellia sinensis – leaf

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.[19]

The mean theobromine concentrations in cocoa and carob products are:[20][21]

Item Mean theobromine per 100 g
Cocoa powder 2060 mg
Cocoa beverages 266 mg
Chocolate toppings 195 mg
Chocolate bakery products 147 mg
Cocoa cereals 69.5 mg
Chocolate ice creams 62.1 mg
Chocolate milks 22.6 mg
Carob products 0.00–50.4 mg

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.[22]

Pharmacology
Caffeine is metabolized in the liver into three primary metabolites: paraxanthine (84%), theobromine (12%), and theophylline (4%)

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.[23]

In the liver, theobromine is metabolized into xanthine and subsequently into methyluric acid.[24] Important enzymes include CYP1A2 and CYP2E1.[25] The elimination half life of theobromine is between 6 to 8 hours.[1][2]

Unlike caffeine, which is highly water soluble, theobromine is only slightly water soluble and is more fat soluble, and thus peaks more slowly in the blood. While caffeine peaks after only 30 minutes, theobromine requires 2-3 hours to peak.[26]

"The main mechanism of action for methylxanthines has long been established as an inhibition of adenosine receptors".[4] Its effect as a phosphodiesterase inhibitor[27] is thought to be small.[4]

Effects
See also: Theobromine poisoning

Humans

Theobromine has no significant stimulant effect on the human central nervous system.[5] It is a bronchodilator and causes relaxation of vascular smooth muscle.[5] It is not currently used as a prescription drug.[4] The amount of theobromine found in chocolate is small enough that chocolate can, in general, be safely consumed by humans.

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.[5][28] The potential phosphodiesterase inhibitory effect of theobromine is seen only at amounts much higher than what people normally would consume in a typical diet including chocolate.[29]

Toxicity

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.[30]

Also, chocolate may be a factor for heartburn in some people because theobromine may affect the esophageal sphincter muscle in a way that permits stomach acids to enter the esophagus.[31]

Animals

Theobromine is the reason chocolate is poisonous to dogs. Dogs and other animals that metabolize theobromine (found in chocolate) more slowly[32] 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,[33] although cats are less likely to ingest sweet food, with most cats having no sweet taste receptors.[34] 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.[35] Although not common, the effects of theobromine poisoning can be fatal.

See also

References
  1. Drouillard, Dennis D.; Vesell, Elliot S.; Dvorchik, Barry H. (March 1978). "Studies on theobromine disposition in normal subjects; Alterations induced by dietary abstention from or exposure to methylxanthines". Clinical Pharmacology & Therapeutics. 23 (3): 296–302. doi:10.1002/cpt1978233296. PMID 627135. S2CID 10519385.
  2. Lelo, A.; Birkett, Dj; Robson, Ra; Miners, Jo (August 1986). "Comparative pharmacokinetics of caffeine and its primary demethylated metabolites paraxanthine, theobromine and theophylline in man". British Journal of Clinical Pharmacology. 22 (2): 177–182. doi:10.1111/j.1365-2125.1986.tb05246.x. PMC 1401099. PMID 3756065.
  3. Ford, K. A.; Ebisuzaki, Y.; Boyle, P. D. (1998). "Methylxanthines. II. Anhydrous Theobromine". Acta Crystallographica Section C Crystal Structure Communications. 54 (12): 1980–1983. doi:10.1107/S0108270198009469.
  4. Smit HJ (2011). "Theobromine and the pharmacology of cocoa". Handbook of Experimental Pharmacology. 200 (200): 201–234. doi:10.1007/978-3-642-13443-2_7. ISBN 978-3-642-13442-5. PMID 20859797.
  5. "Theobromine". PubChem, US National Library of Medicine. 27 August 2022. Retrieved 3 September 2022.
  6. Baer DM, Pinkston EM (1997). Environment and Behavior. Westview Press. p. 200. ISBN 978-0813331591.
  7. von Bibra E, Ott J (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. Archived from the original on 2019-09-18. Retrieved 2015-12-12.
  8. Woskresensky A (1842). "Über das Theobromin". Liebigs Annalen der Chemie und Pharmacie. 41: 125–127. doi:10.1002/jlac.18420410117. Archived from the original on 2016-06-10. Retrieved 2015-12-12.
  9. Thorpe TE (1902). Essays in Historical Chemistry. The MacMillan Company.
  10. Fischer, Emil (1882). "Umwandlung des Xanthin in Theobromin und Caffein". Berichte der Deutschen Chemischen Gesellschaft. 15 (1): 453–456. doi:10.1002/cber.18820150194. Archived (PDF) from the original on 2019-05-05. Retrieved 2019-09-09.
  11. Fischer E (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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  16. "USDA Nutrient database, entries for dark chocolate". Retrieved 2012-11-07.
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  20. "FoodData Central". fdc.nal.usda.gov.
  21. Craig WJ, Nguyen TT (1984). "Caffeine and theobromine levels in cocoa and carob products". Journal of Food Science. 49 (1): 302–303. doi:10.1111/j.1365-2621.1984.tb13737.x. 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.
  22. Ashihara H, Yokota T, Crozier A (2013). "Biosynthesis and catabolism of purine alkaloids". New Light on Alkaloid Biosynthesis and Future Prospects. Advances in Botanical Research. Vol. 68. pp. 111–138. doi:10.1016/B978-0-12-408061-4.00004-3. ISBN 9780124080614.
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  35. "HEALTH WATCH: How to Avoid a Canine Chocolate Catastrophe!". The News Letter. Belfast, Northern Ireland. 2005-03-01.
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