Theobromine, also known as xantheose, is the principal

alkaloid Alkaloids are a broad class of natural product, naturally occurring organic compounds that contain at least one nitrogen atom. Some synthetic compounds of similar structure may also be termed alkaloids. Alkaloids are produced by a large varie ...

of ''

Theobroma cacao ''Theobroma cacao'' (cacao tree or cocoa tree) is a small ( tall) evergreen tree in the Malvaceae family. Its seedscocoa beansare used to make chocolate liquor, cocoa solids, cocoa butter and chocolate. Although the tree is native to the tropi ...

'' (cacao plant). Theobromine is slightly water-

soluble In chemistry, solubility is the ability of a substance, the solute, to form a solution with another substance, the solvent. Insolubility is the opposite property, the inability of the solute to form such a solution. The extent of the solubi ...

(330 mg/L) with a bitter taste. In industry, theobromine is used as an

additive Additive may refer to: Mathematics * Additive function, a function in number theory * Additive map, a function that preserves the addition operation * Additive set-function see Sigma additivity * Additive category, a preadditive category with fin ...

and precursor to some

cosmetics Cosmetics are substances that are intended for application to the body for cleansing, beautifying, promoting attractiveness, or altering appearance. They are mixtures of chemical compounds derived from either Natural product, natural source ...

. It is found in

chocolate Chocolate is a food made from roasted and ground cocoa beans that can be a liquid, solid, or paste, either by itself or to flavoring, flavor other foods. Cocoa beans are the processed seeds of the cacao tree (''Theobroma cacao''); unprocesse ...

, as well as in a number of other foods, including

tea Tea is an aromatic beverage prepared by pouring hot or boiling water over cured or fresh leaves of '' Camellia sinensis'', an evergreen shrub native to East Asia which probably originated in the borderlands of south-western China and nor ...

(''

Camellia sinensis ''Camellia sinensis'' is a species of evergreen shrub or small tree in the flowering plant family Theaceae. Its leaves, leaf buds, and stems can be used to produce tea. Common names include tea plant, tea shrub, and tea tree (unrelated to ''Me ...

''), some American

hollies The Hollies are an English rock and pop band formed in Manchester in 1962. One of the leading British groups of the 1960s and into the mid-1970s, they are known for their distinctive three-part vocal harmony style. Singer Allan Clarke and rh ...

(

yaupon ''Ilex vomitoria'', commonly known as yaupon () or yaupon holly, is a species of holly that is native to southeastern North America. The word yaupon was derived from the Catawban ''yą́pą'', from ''yą-'' tree + ''pą'' leaf. Another common n ...

and

guayusa ''Ilex guayusa'' ( or ) is a species of tree of the holly genus, native to the Amazon Rainforest. One of four known caffeinated holly trees, the leaves of the guayusa tree are harvested fresh and brewed like a tea for their stimulative effects. I ...

) and the

kola nut The kola nut ( Yoruba: ''obi'', Dagbani: ''guli'', Hausa: goro, Igbo: ''ọjị'', Sängö: ''gôro,'' Swahili: ''mukezu'') is the seed of certain species of plant of the genus ''Cola'', placed formerly in the cocoa family Sterculiaceae and ...

. It is a white or colourless solid, but commercial samples can appear yellowish. Theobromine, a metabolite of

caffeine Caffeine is a central nervous system (CNS) stimulant of the methylxanthine chemical classification, class and is the most commonly consumed Psychoactive drug, psychoactive substance globally. It is mainly used for its eugeroic (wakefulness pr ...

, is processed in the

liver The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...

into

xanthine Xanthine ( or , from Ancient Greek for its yellowish-white appearance; archaically xanthic acid; systematic name 3,7-dihydropurine-2,6-dione) is a purine base found in most human body tissues and fluids, as well as in other organisms. Several ...

and methyluric acid, peaks in the blood 2–3 hours after ingestion due to its fat solubility, and primarily acts by inhibiting

adenosine receptor The adenosine receptors (or P1 receptors) are a class of Purinergic receptor, purinergic G protein-coupled receptors with adenosine as the endogenous ligand (biochemistry), ligand. There are four known types of adenosine receptors in humans: Aden ...

s with minor

phosphodiesterase A phosphodiesterase (PDE) is an enzyme that breaks a phosphodiester bond. Usually, ''phosphodiesterase'' refers to cyclic nucleotide phosphodiesterases, which have great clinical significance and are described below. However, there are many oth ...

inhibition. It is a mild

heart The heart is a muscular Organ (biology), organ found in humans and other animals. This organ pumps blood through the blood vessels. The heart and blood vessels together make the circulatory system. The pumped blood carries oxygen and nutrie ...

stimulant and

bronchodilator A bronchodilator or broncholytic (although the latter occasionally includes secretory inhibition as well) is a substance that dilates the bronchi and bronchioles, decreasing resistance in the respiratory airway and increasing airflow to the lun ...

humans Humans (''Homo sapiens'') or modern humans are the most common and widespread species of primate, and the last surviving species of the genus ''Homo''. They are Hominidae, great apes characterized by their Prehistory of nakedness and clothing ...

with limited

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...

effects. It can be toxic or fatal to

animals Animals are multicellular, eukaryotic organisms in the biological kingdom Animalia (). With few exceptions, animals consume organic material, breathe oxygen, have myocytes and are able to move, can reproduce sexually, and grow from a ...

dogs The dog (''Canis familiaris'' or ''Canis lupus familiaris'') is a domesticated descendant of the gray wolf. Also called the domestic dog, it was selectively bred from a population of wolves during the Late Pleistocene by hunter-gatherers ...

and

cats The cat (''Felis catus''), also referred to as the domestic cat or house cat, is a small domesticated carnivorous mammal. It is the only domesticated species of the family Felidae. Advances in archaeology and genetics have shown that the ...

due to their slower

metabolism Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...

of the compound.

Structure

Theobromine is a flat molecule, a derivative of

purine Purine is a heterocyclic aromatic organic compound that consists of two rings (pyrimidine and imidazole) fused together. It is water-soluble. Purine also gives its name to the wider class of molecules, purines, which include substituted puri ...

and an isomer of theophylline. It is also classified as a

dimethyl Ethane ( , ) is a naturally occurring organic chemical compound with chemical formula . At standard temperature and pressure, ethane is a colorless, odorless gas. Like many hydrocarbons, ethane is isolated on an industrial scale from natural ...

. Related compounds include

theophylline Theophylline, also known as 1,3-dimethylxanthine, is a drug that inhibits phosphodiesterase and blocks adenosine receptors. It is used to treat chronic obstructive pulmonary disease (COPD) and asthma. Its pharmacology is similar to other met ...

paraxanthine Paraxanthine, also known as 1,7-dimethylxanthine, is an isomer of theophylline and theobromine, two well-known stimulants found in coffee, tea, and chocolate, mainly in the form of caffeine. It is a member of the xanthine family of alkaloids, ...

, and 7-methylxanthine, each of which differ in the number or placement of the methyl groups.

History

Theobromine was first discovered in 1841 in cacao beans by the chemist A. Woskresensky. Synthesis of theobromine from

was first reported in 1882 by

Hermann Emil Fischer Hermann Emil Louis Fischer (; 9 October 1852 – 15 July 1919) was a German chemist and List of Nobel laureates in Chemistry, 1902 recipient of the Nobel Prize in Chemistry. He discovered the Fischer esterification. He also developed the Fisch ...

Etymology

''Theobromine'' is derived from ''

Theobroma ''Theobroma'' is a genus of flowering plants in the mallow family, Malvaceae. It was previously classified as a member of Sterculiaceae, which has been incorporated into Malvaceae to make it monophyletic. It contains roughly 20 species of smal ...

'', the name of the

genus Genus (; : genera ) is a taxonomic rank above species and below family (taxonomy), family as used in the biological classification of extant taxon, living and fossil organisms as well as Virus classification#ICTV classification, viruses. In bino ...

of the cacao tree, with the suffix ''-ine'' given to alkaloids and other

basic Basic or BASIC may refer to: Science and technology * BASIC, a computer programming language * Basic (chemistry), having the properties of a base * Basic access authentication, in HTTP Entertainment * Basic (film), ''Basic'' (film), a 2003 film ...

nitrogen-containing compounds. That name in turn is made up of the

Greek Greek may refer to: Anything of, from, or related to Greece, a country in Southern Europe: *Greeks, an ethnic group *Greek language, a branch of the Indo-European language family **Proto-Greek language, the assumed last common ancestor of all kno ...

roots ''theo'' ("

god In monotheistic belief systems, God is usually viewed as the supreme being, creator, and principal object of faith. In polytheistic belief systems, a god is "a spirit or being believed to have created, or for controlling some part of the un ...

") and ''broma'' ("food"), meaning "food of the gods". (note: the book incorrectly states that the name "theobroma" is derived from Latin) Despite its name, the compound contains no

bromine Bromine is a chemical element; it has chemical symbol, symbol Br and atomic number 35. It is a volatile red-brown liquid at room temperature that evaporates readily to form a similarly coloured vapour. Its properties are intermediate between th ...

, which is based on Greek ''bromos'' ("stench").

Sources

Theobromine is the primary alkaloid found in

cocoa Cocoa may refer to: Chocolate * Chocolate * ''Theobroma cacao'', the cocoa tree * Cocoa bean, seed of ''Theobroma cacao'' * Chocolate liquor, or cocoa liquor, pure, liquid chocolate extracted from the cocoa bean, including both cocoa butter and ...

and

Cocoa butter Cocoa butter, also called theobroma oil, is a pale-yellow, edible Vegetable oil, fat extracted from the cocoa bean (''Theobroma cacao''). It is used to make chocolate, as well as some ointments, toiletries, and pharmaceuticals. Cocoa butter h ...

only contains trace amounts of theobromine. There are usually higher concentrations in dark than in milk chocolate. There are approximately of theobromine in of milk chocolate, while the same amount of dark chocolate contains about . Cocoa beans naturally contain approximately 1% theobromine. Plant species and components with substantial amounts of theobromine are: * ''

'' – seed and

seed coat In botany, a seed is a plant structure containing an embryo and stored nutrients in a protective coat called a ''testa''. More generally, the term "seed" means anything that can be sown, which may include seed and husk or tuber. Seeds are the ...

* ''

Theobroma bicolor ''Theobroma bicolor'', known commonly as the mocambo tree, jaguar tree, balamte, or pataxte, among various other common names, is a tree in the genus '' Theobroma'' (family Malvaceae), which also contains the better-known ''Theobroma cacao'' (coc ...

'' – seed coat * ''

Ilex paraguariensis Yerba mate or yerba maté (), ''Ilex paraguariensis'', is a plant species of the holly genus native to South America. It was named by the French botanist Augustin Saint-Hilaire. The leaves of the plant can be steeped in hot water to make a bev ...

'' – leaf * ''

Ilex guayusa ''Ilex guayusa'' ( or ) is a species of tree of the holly genus, native to the Amazon Rainforest. One of four known caffeinated holly trees, the leaves of the guayusa tree are harvested fresh and brewed like a tea for their stimulative effects. I ...

'' – leaf * ''

Ilex vomitoria ''Ilex vomitoria'', commonly known as yaupon () or yaupon holly, is a species of holly that is native to southeastern North America. The word yaupon was derived from the Catawban ''yą́pą'', from ''yą-'' tree + ''pą'' leaf. Another common n ...

'' – leaf * ''

'' – leaf Theobromine can also be found in trace amounts in the

, the

guarana Guaraná ( from the Portuguese ''guaraná'' ; ''Paullinia cupana'', syns. ''P. crysan, P. sorbilis'') is a climbing plant in the family Sapindaceae, native to the Amazon basin and especially common in Brazil. Guaraná has large leaves and clu ...

berry,

yerba mate Yerba mate or yerba maté (), ''Ilex paraguariensis'', is a plant species of the holly genus native to South America. It was named by the French botanist Augustin Saint-Hilaire. The leaves of the plant can be steeped in hot water to make a bev ...

(''

''), and the

tea plant ''Camellia sinensis'' is a species of evergreen shrub or small tree in the flowering plant family Theaceae. Its leaves, leaf buds, and stems can be used to produce tea. Common names include tea plant, tea shrub, and tea tree (unrelated to '' M ...

. The mean theobromine concentrations in cocoa and

carob The carob ( ; ''Ceratonia siliqua'') is a flowering evergreen tree or shrub in the Caesalpinioideae sub-family of the legume family, Fabaceae. It is widely cultivated for its edible fruit, which takes the form of seed pods, and as an ornam ...

products are:

Biosynthesis

Theobromine is a purine alkaloid derived from

xanthosine Xanthosine is a nucleoside derived from xanthine and ribose. It is the biosynthetic precursor to 7-methylxanthosine by the action of 7-methylxanthosine synthase. 7-Methylxanthosine in turn is the precursor to theobromine (active alkaloid in cho ...

, a

nucleoside Nucleosides are glycosylamines that can be thought of as nucleotides without a phosphate group. A nucleoside consists simply of a nucleobase (also termed a nitrogenous base) and a five-carbon sugar (ribose or 2'-deoxyribose) whereas a nucleotid ...

. 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

Pharmacology

Even without dietary intake, theobromine may occur in the body as it is a product of the human metabolism of

, which is

metabolised Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...

in the liver into 12% theobromine, 4%

, and 84%

. In the liver, theobromine is metabolized into

and subsequently into methyluric acid. Important enzymes include

CYP1A2 Cytochrome P450 1A2 (abbreviated CYP1A2), a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the human body. In humans, the CYP1A2 enzyme is encoded by the ''CYP1A2'' gene. Function ...

and

CYP2E1 Cytochrome P450 2E1 (abbreviated CYP2E1, ) is a member of the cytochrome P450 mixed-function oxidase system, which is involved in the metabolism of xenobiotics in the body. This class of enzymes is divided up into a number of subcategories, inclu ...

. The elimination half life of theobromine is between 6 and 8 hours. 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. The primary mechanism of action for theobromine inside the body is inhibition of

adenosine Adenosine (symbol A) is an organic compound that occurs widely in nature in the form of diverse derivatives. The molecule consists of an adenine attached to a ribose via a β-N9- glycosidic bond. Adenosine is one of the four nucleoside build ...

receptors. Its effect as a

phosphodiesterase inhibitor A phosphodiesterase inhibitor is a drug that blocks one or more of the five subtypes of the enzyme phosphodiesterase (PDE), thereby preventing the inactivation of the intracellular second messengers, cyclic adenosine monophosphate (cAMP) and cycl ...

is thought to be small.

Effects

Humans

Theobromine is a heart stimulator and

diuretic A diuretic () is any substance that promotes diuresis, the increased production of urine. This includes forced diuresis. A diuretic tablet is sometimes colloquially called a water tablet. There are several categories of diuretics. All diuretics ...

but has no significant stimulant effect on the human central nervous system. It is a

and causes relaxation of

vascular smooth muscle Vascular smooth muscle is the type of smooth muscle that makes up most of the walls of blood vessels. Structure Vascular smooth muscle refers to the particular type of smooth muscle found within, and composing the majority of the wall of blood v ...

. It is available as a

prescription drug A prescription drug (also prescription medication, prescription medicine or prescription-only medication) is a pharmaceutical drug that is permitted to be dispensed only to those with a medical prescription. In contrast, over-the-counter drugs c ...

in South Korea. The amount of theobromine found in chocolate is small enough that chocolate can, in general, be safely consumed by humans. Compared with caffeine, theobromine is weaker in both its inhibition of

cyclic nucleotide A cyclic nucleotide (cNMP) is a single-phosphate nucleotide with a cyclic bond arrangement between the sugar and phosphate groups. Like other nucleotides, cyclic nucleotides are composed of three functional groups: a sugar, a nitrogenous base, ...

phosphodiesterases A phosphodiesterase (PDE) is an enzyme that breaks a phosphodiester bond. Usually, ''phosphodiesterase'' refers to cyclic nucleotide phosphodiesterases, which have great clinical significance and are described below. However, there are many oth ...

and its antagonism of

adenosine receptors The adenosine receptors (or P1 receptors) are a class of purinergic G protein-coupled receptors with adenosine as the endogenous ligand. There are four known types of adenosine receptors in humans: A1, A2A, A2B and A3; each is encoded by a di ...

. The potential

y effect of theobromine is seen only at amounts much higher than what people normally would consume in a typical diet including chocolate.

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. Also, chocolate may be a factor for

heartburn Heartburn is a burning sensation felt behind the breastbone. It is a symptom that is commonly linked to acid reflux and is often triggered by food, particularly fatty, sugary, spicy, chocolate, citrus, onion-based and tomato-based products. Ly ...

in some people because theobromine may affect the

esophageal sphincter The esophagus (American English), oesophagus (British English), or œsophagus ( archaic spelling) ( see spelling difference) all ; : ((o)e)(œ)sophagi or ((o)e)(œ)sophaguses), colloquially known also as the food pipe, food tube, or gullet, ...

muscle in a way that permits stomach acids to enter the

esophagus The esophagus (American English), oesophagus (British English), or œsophagus (Œ, archaic spelling) (American and British English spelling differences#ae and oe, see spelling difference) all ; : ((o)e)(œ)sophagi or ((o)e)(œ)sophaguses), c ...

Animals

Theobromine is the reason chocolate is poisonous to dogs. Dogs and other animals that

metabolize Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the ...

theobromine (found in chocolate) more slowly can succumb to theobromine poisoning from as little as of

milk chocolate Milk chocolate is a form of solid chocolate containing Chocolate liquor, cocoa, sugar and milk. It is the most consumed types of chocolate, type of chocolate, and is used in a wide diversity of chocolate bar, bars, tablets and other confectione ...

for a smaller dog and , or around nine small milk chocolate bars, for an average-sized dog. The concentration of theobromine in dark chocolates (about ) is up to 10 times that of milk chocolate (), meaning dark chocolate is far more toxic to dogs per unit weight or volume than milk chocolate. The

median lethal dose In toxicology, the median lethal dose, LD50 (abbreviation for " lethal dose, 50%"), LC50 (lethal concentration, 50%) or LCt50 is a toxic unit that measures the lethal dose of a given substance. The value of LD50 for a substance is the dose re ...

of theobromine for dogs is ; therefore, a dog would need to consume a minimum of of the most theobromine-rich () dark chocolate, or a maximum of (of theobromine-rich milk chocolate), to have a 50% chance of receiving a lethal dose. However, even of milk chocolate may induce vomiting and diarrhea. The same risk is reported for cats as well, although cats are less likely to ingest sweet food, as cats lack sweet taste receptors. Complications include digestive issues, dehydration, excitability, and a slow heart rate. Later stages of theobromine poisoning include

epileptic Epilepsy is a group of non-communicable neurological disorders characterized by a tendency for recurrent, unprovoked seizures. A seizure is a sudden burst of abnormal electrical activity in the brain that can cause a variety of symptoms, rang ...

-like

seizure A seizure is a sudden, brief disruption of brain activity caused by abnormal, excessive, or synchronous neuronal firing. Depending on the regions of the brain involved, seizures can lead to changes in movement, sensation, behavior, awareness, o ...

s and death. If caught early on, theobromine poisoning is treatable. Although not common, the effects of theobromine poisoning can be fatal.

References

{{Phosphodiesterase inhibitors Adenosine receptor antagonists Bitter compounds Components of chocolate IARC Group 3 carcinogens Phosphodiesterase inhibitors Xanthines Human drug metabolites

Structure

History

Etymology

Sources

Biosynthesis

Pharmacology

Effects

Humans

Toxicity

Animals

See also

References