Theobromine

Systematic (IUPAC) name
3,7-dimethyl-1H-purine-2,6-dione
Clinical data
Pregnancy cat.	?
Legal status	Uncontrolled substance
Routes	Oral
Pharmacokinetic data
Metabolism	Hepatic demethylation and oxidation[1]
Half-life	7.1 +/- 0.7 hours
Excretion	Renal (10% unchanged, rest as metabolites)[1]
Identifiers
CAS number	83-67-0 Y
ATC code	C03BD01 R03DA07
PubChem	CID 5429
DrugBank	DB01412
ChemSpider	5236 Y
UNII	OBD445WZ5P Y
KEGG	C07480 N
ChEBI	CHEBI:28946 Y
ChEMBL	CHEMBL1114 Y
Synonyms	xantheose diurobromine 3,7-dimethylxanthine
Chemical data
Formula	C7H8N4O2[2]
Mol. mass	180.164 g/mol
SMILES	eMolecules & PubChem
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
N (what is this?)  (verify)

Theobromine (theobromide^[3]), also known as xantheose,^[2] is a bitter alkaloid of the cacao plant, with the chemical formula C₇H₇N₄O₂. It is found in chocolate, as well as in a number of other foods, including the leaves of the tea plant, and the kola (or cola) nut. It is in the methylxanthine class of chemical compounds,^[4] which also includes the similar compounds theophylline and caffeine.^[2] (In caffeine, the only difference is that the NH group of theobromine is an N-CH₃ group.) 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")^[5] with the suffix -ine given to alkaloids and other basic nitrogen-containing compounds.^[6]

Theobromine is a slightly water-soluble (330 mg/L^[7]), crystalline, bitter powder; the colour has been listed as either white or colourless.^[8] It has a similar, but lesser, effect than 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.^[9]

Theobromine was first discovered in 1841^[10] in cacao beans by Russian chemist Alexander Woskresensky.^[11] Theobromine was first synthesized from xanthine by Hermann Emil Fischer.^[12][13]

Sources[link]

A chocolate bar and melted 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 powder can vary in the amount of theobromine, from 2%^[14] theobromine to at least 10% usually having higher concentrations in "dark" than "milk" chocolate.^[15] Theobromine can also be found in small amounts in the kola nut (1.0-2.5%), the guarana berry, Ilex guayusa, Ilex paraguariensis (yerba mate), and the tea plant.^[16]

The plant species with the largest amounts of theobromine are:^[17]

• Theobroma cacao
• Theobroma bicolor
• Ilex paraguariensis
• Camellia sinensis
• Cola acuminata
• Theobroma angustifolium
• Guarana
• Coffea arabica

The mean theobromine concentrations in cocoa and carob products are:^[18]

Therapeutic uses[link]

In modern medicine, theobromine is used as a vasodilator (a blood vessel widener), a diuretic (urination aid), and heart stimulant.^[2]

Theobromine increases urine production. Because of this diuretic effect, and its ability to dilate blood vessels, theobromine has been used to treat high blood pressure.^[19] The American Journal of Clinical Nutrition notes that historic use of theobromine as a treatment for other circulatory problems including arteriosclerosis, certain vascular diseases, angina pectoris, and hypertension should be considered in future studies.^[20]

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.^[21]

"In the human body, theobromine levels are halved between 6-10 hours after consumption."^[19]

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.^[22] Possible future uses of theobromine in such fields as cancer prevention have been patented.^[23]

Pharmacology[link]

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.^[24]

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

Like other methylated xanthine derivatives, theobromine is both a

1. competitive nonselective phosphodiesterase inhibitor,^[27] which raises intracellular cAMP, activates PKA, inhibits TNF-alpha^[28][29] and leukotriene^[30] synthesis, and reduces inflammation and innate immunity^[30] and
2. nonselective adenosine receptor antagonist.^[31]

As a phosphodiesterase inhibitor, theobromine helps prevent the phosphodiesterase enzymes from converting the active cAMP to an inactive form.^[32] 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 that stimulated the production of cAMP are much longer-lived. In general, the net result is a stimulatory effect.^[33]

Effects[link]

Humans[link]

A diagram of the bronchus. The loosening of the muscles in the bronchus caused by theobromine helps alleviate the symptoms of asthma.

The amount of theobromine found in chocolate is small enough that chocolate can, in general, be safely consumed by humans. However, theobromine poisoning may result from the chronic or acute consumption of large quantities, especially in the elderly.^[34]

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 receptors.^[35] Therefore, theobromine has a lesser impact on the human central nervous system than caffeine. However, theobromine stimulates the heart to a greater degree.^[36] While theobromine is not as addictive, it has been cited as possibly causing addiction to chocolate.^[37] Theobromine has also been identified as one of the compounds contributing to chocolate's reputed role as an aphrodisiac.^[38]

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.^[39] However, a recent paper published suggested that the decrease in blood pressure may be caused by flavanols.^[20] Furthermore, its draining effect allows it to be used to treat cardiac failure, which leads to and is exacerbated by an excessive accumulation of fluid in the body.^[39]

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.^[40] In the study, theobromine significantly increased the capsaicin concentration required to induce coughs when compared with a placebo.^[40] A drug, called BC1036, is being developed by the private UK company SEEK and it uses theobromine to treat persistent cough.^[41] In addition, theobromine is helpful in treating asthma, since it relaxes the smooth muscles, including the ones found in the bronchi.^[42]

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.^[43] This association was not found to be linear for aggressive tumors.^[43] While the association may be spurious, it is plausible.^[43] Prenatal and infant exposure to theobromine appeared possibly associated with hypospadias and testicular cancer in one population study.^[44]

As with caffeine, theobromine can cause sleeplessness, tremors, restlessness, anxiety, as well as contribute to increased production of urine.^[42] Additional side effects include loss of appetite, nausea, and vomiting.^[45]

Danger for animals[link]

Animals that metabolize theobromine more slowly, such as dogs, can succumb to theobromine poisoning from as little as 50 grams (1.8 oz) of chocolate for a smaller dog and 400 grams (14.4 oz) 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.^[46] 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.^[47] Although not usual, the effects of theobromine poisoning, as stated, can become fatal.

The toxicity for (pet) birds is not known, but it is typically assumed that it is toxic to birds.^[48]

Other[link]

Theobromine is known to induce gene mutations in lower eukaryotes and bacteria. At the time of a 1991 report, further updated in 1997, by the IARC, genetic mutations had been found in higher eukaryotic cells, specifically cultured mammalian cells, but the compound was still listed as having inadequate evidence for classification of human carcinogenicity.^[49]

See also[link]

• History of chocolate
• Theobromine poisoning

References[link]

Further reading[link]

• [1] from the Hazardous Substances Data Bank