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Record Information
Version3.6
Creation Date2006-05-22 15:12:12 UTC
Update Date2016-02-11 01:05:49 UTC
HMDB IDHMDB02825
Secondary Accession NumbersNone
Metabolite Identification
Common NameTheobromine
DescriptionTheobromine, or 3,7-Dimethylxanthine, is the principle alkaloid in Theobroma cacao (the cacao bean) and other plants. A xanthine alkaloid that is used as a bronchodilator and as a vasodilator. It has a weaker diuretic activity than theophylline and is also a less powerful stimulant of smooth muscle. It has practically no stimulant effect on the central nervous system. It was formerly used as a diuretic and in the treatment of angina pectoris and hypertension. (From Martindale, The Extra Pharmacopoeia, 30th ed, pp1318-9, as cited on Pubchem). Theobromine is a bitter alkaloid of the methylxanthine family, which also includes the similar compounds theophylline and caffeine. Despite its name, the compound contains no bromine. Theobromine is derived from Theobroma, the genus of the cacao tree, which is composed of the Greek roots theo ("God") and broma ("food"), meaning "food of the gods". It is the primary alkaloid found in cocoa and chocolate, and is one of the causes for chocolate's mood-elevating effects. The amount found in chocolate is small enough that chocolate can be safely consumed by humans in large quantities, but animals that metabolize theobromine more slowly, such as cats and dogs, can easily consume enough chocolate to cause chocolate poisoning. Theobromine is a stimulant frequently confused with caffeine. Theobromine has very different effects on the human body from caffeine; it is a mild, lasting stimulant with a mood improving effect, whereas caffeine has a strong, immediate effect and increases stress. In medicine, it is used as a diuretic, vasodilator, and myocardial stimulant. There is a possible association between prostate cancer and theobromine. Theobromine is a contributing factor in acid reflux because it relaxes the esophageal sphincter muscle, allowing stomach acid access to the esophagus (Wikipedia).
Structure
Thumb
Synonyms
ValueSource
3,7-dihydro-3,7-Dimethyl-1H-purine-2,6-dioneChEBI
3,7-Dimethylpurine-2,6-dioneChEBI
3,7-DimethylxanthineChEBI
TheobrominChEBI
TeobrominHMDB
2,6-Dihydroxy-3,7-dimethyl-purineHMDB
3,7-Dimethyl-xanthineHMDB
DiurobromineHMDB
Chemical FormulaC7H8N4O2
Average Molecular Weight180.164
Monoisotopic Molecular Weight180.06472552
IUPAC Name3,7-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione
Traditional Nametheobromine
CAS Registry Number83-67-0
SMILES
CN1C=NC2=C1C(=O)NC(=O)N2C
InChI Identifier
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)
InChI KeyInChIKey=YAPQBXQYLJRXSA-UHFFFAOYSA-N
Chemical Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as alkaloids and derivatives. These are naturally occurring chemical compounds that contain mostly basic nitrogen atoms. This group also includes some related compounds with neutral and even weakly acidic properties. Also some synthetic compounds of similar structure are attributed to alkaloids. In addition to carbon, hydrogen and nitrogen, alkaloids may also contain oxygen, sulfur and more rarely other elements such as chlorine, bromine, and phosphorus.
KingdomOrganic compounds
Super ClassAlkaloids and derivatives
ClassNot Available
Sub ClassNot Available
Direct ParentAlkaloids and derivatives
Alternative Parents
Substituents
  • Alkaloid or derivatives
  • Xanthine
  • Purinone
  • 6-oxopurine
  • Purine
  • Imidazopyrimidine
  • Pyrimidone
  • Pyrimidine
  • N-substituted imidazole
  • Heteroaromatic compound
  • Vinylogous amide
  • Imidazole
  • Azole
  • Urea
  • Lactam
  • Azacycle
  • Organoheterocyclic compound
  • Hydrocarbon derivative
  • Organooxygen compound
  • Organonitrogen compound
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External Descriptors
Ontology
StatusDetected and Quantified
Origin
  • Drug metabolite
  • Plant
Biofunction
  • Waste products
ApplicationNot Available
Cellular locations
  • Cytoplasm (predicted from logP)
Physical Properties
StateSolid
Experimental Properties
PropertyValueReference
Melting Point357 °CNot Available
Boiling PointNot AvailableNot Available
Water Solubility0.33 mg/mL at 25 °CNot Available
LogP-0.78HANSCH,C ET AL. (1995)
Predicted Properties
PropertyValueSource
Water Solubility9.74 mg/mLALOGPS
logP-0.46ALOGPS
logP-0.77ChemAxon
logS-1.3ALOGPS
pKa (Strongest Acidic)9.28ChemAxon
pKa (Strongest Basic)-0.91ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area67.23 Å2ChemAxon
Rotatable Bond Count0ChemAxon
Refractivity44.93 m3·mol-1ChemAxon
Polarizability16.85 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash Key
GC-MSGC-MS Spectrum - GC-MS (1 TMS)splash10-0079-7980000000-efb14ee11aad17b6b4d2View in MoNA
LC-MS/MSLC-MS/MS Spectrum - Quattro_QQQ 10V, Positive (Annotated)splash10-001i-0900000000-8d639c53ad9b2b8f508eView in MoNA
LC-MS/MSLC-MS/MS Spectrum - Quattro_QQQ 25V, Positive (Annotated)splash10-014i-9300000000-0d20b5fe9b93b113a29eView in MoNA
LC-MS/MSLC-MS/MS Spectrum - Quattro_QQQ 40V, Positive (Annotated)splash10-014l-9000000000-55968ca3e94ce5a05cfeView in MoNA
LC-MS/MSLC-MS/MS Spectrum - EI-B (Unknown) , Positivesplash10-001i-6900000000-7d44855bbf11e559d96eView in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 10V, Positivesplash10-001i-1900000000-1932568f11357ae32f55View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 20V, Positivesplash10-001i-2900000000-3918185c5a4afb18f11aView in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 30V, Positivesplash10-0910-5900000000-b590772083f824ea0fc6View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 40V, Positivesplash10-014i-9400000000-c06ac99fd6e0c84d9653View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 50V, Positivesplash10-014i-9100000000-3802e577174b5a4accedView in MoNA
MSMass Spectrum (Electron Ionization)splash10-001i-9700000000-770b2dc556ada7d97caeView in MoNA
1D NMR1H NMR SpectrumNot Available
2D NMR[1H,13C] 2D NMR SpectrumNot Available
Biological Properties
Cellular Locations
  • Cytoplasm (predicted from logP)
Biofluid Locations
  • Blood
  • Cerebrospinal Fluid (CSF)
  • Saliva
  • Urine
Tissue Location
  • Kidney
  • Liver
Pathways
NameSMPDB LinkKEGG Link
Caffeine MetabolismSMP00028map00232
Normal Concentrations
BiofluidStatusValueAgeSexConditionReferenceDetails
BloodDetected and Quantified1.1 +/- 0.2 uMAdult (>18 years old)MaleNormal details
SalivaDetected but not QuantifiedNot ApplicableAdult (>18 years old)Male
Normal
details
SalivaDetected but not QuantifiedNot ApplicableAdult (>18 years old)Male
Normal
details
SalivaDetected but not QuantifiedNot ApplicableAdult (>18 years old)Male
Normal
details
SalivaDetected but not QuantifiedNot ApplicableAdult (>18 years old)Male
Normal
details
SalivaDetected but not QuantifiedNot ApplicableAdult (>18 years old)Male
Normal
details
SalivaDetected but not QuantifiedNot ApplicableAdult (>18 years old)Male
Normal
details
SalivaDetected but not QuantifiedNot ApplicableAdult (>18 years old)Male
Normal
details
SalivaDetected but not QuantifiedNot ApplicableAdult (>18 years old)Male
Normal
details
SalivaDetected but not QuantifiedNot ApplicableAdult (>18 years old)Male
Normal
details
SalivaDetected but not QuantifiedNot ApplicableAdult (>18 years old)Male
Normal
details
SalivaDetected but not QuantifiedNot ApplicableAdult (>18 years old)Not SpecifiedNormal details
UrineDetected but not QuantifiedNot ApplicableAdult (>18 years old)BothNormal details
UrineDetected and Quantified0.5 (0.36-0.7) umol/mmol creatinineAdult (>18 years old)BothNormal details
Abnormal Concentrations
BiofluidStatusValueAgeSexConditionReferenceDetails
BloodDetected and Quantified1.3 +/- 0.5 uMAdult (>18 years old)Male
Malaria
details
Cerebrospinal Fluid (CSF)Detected and Quantified0.869 +/- 0.182 uMAdult (>18 years old)Bothsevere traumatic brain injury (TBI) details
Cerebrospinal Fluid (CSF)Detected and Quantified1.710 +/- 0.539 uMNot SpecifiedNot SpecifiedTraumatic Brain Injury (TBI) details
Cerebrospinal Fluid (CSF)Detected and Quantified0.641 +/- 0.169 uMNot SpecifiedNot SpecifiedTraumatic Brain Injury (TBI) details
Cerebrospinal Fluid (CSF)Detected and Quantified0.863 +/- 0.241 uMNot SpecifiedFemaleTraumatic Brain Injury (TBI) details
Cerebrospinal Fluid (CSF)Detected and Quantified0.886 +/- 0.185 uMNot SpecifiedMaleTraumatic Brain Injury (TBI) details
UrineDetected but not QuantifiedNot ApplicableAdult (>18 years old)BothAutosomal dominant polycystic kidney disease (ADPKD) details
UrineDetected and Quantified3.6 (1.0-7.3) umol/mmol creatinineAdult (>18 years old)Both
Asthma
details
Associated Disorders and Diseases
Disease References
Asthma
  1. Zydron M, Baranowski J, Baranowska I: Separation, pre-concentration, and HPLC analysis of methylxanthines in urine samples. J Sep Sci. 2004 Oct;27(14):1166-72. [15537072 ]
Malaria
  1. Akinyinka OO, Sowunmi A, Honeywell R, Renwick AG: The effects of acute falciparum malaria on the disposition of caffeine and the comparison of saliva and plasma-derived pharmacokinetic parameters in adult Nigerians. Eur J Clin Pharmacol. 2000 May;56(2):159-65. [10877011 ]
Associated OMIM IDs
DrugBank IDDB01412
DrugBank Metabolite IDDBMET00220
Phenol Explorer Compound IDNot Available
Phenol Explorer Metabolite IDNot Available
FoodDB IDFDB000455
KNApSAcK IDC00001509
Chemspider ID5236
KEGG Compound IDC07480
BioCyc ID3-7-DIMETHYLXANTHINE
BiGG IDNot Available
Wikipedia LinkTheobromine
NuGOwiki LinkHMDB02825
Metagene LinkHMDB02825
METLIN ID1456
PubChem Compound5429
PDB ID37T
ChEBI ID28946
References
Synthesis ReferenceYoon, Hye-Sung; Hwang, In-Gyun; Bang, Won-Gi. Production of theobromine from caffeine by Pseudomonas sp. Chayon Chawon Nonjip (1995), 35(1), 33-39.
Material Safety Data Sheet (MSDS)Download (PDF)
General References
  1. Holstege A, Kurz M, Weinbeck M, Gerok W: Excretion of caffeine and its primary degradation products into bile. J Hepatol. 1993 Jan;17(1):67-73. [8445222 ]
  2. Delahunty T, Schoendorfer D: Caffeine demethylation monitoring using a transdermal sweat patch. J Anal Toxicol. 1998 Nov-Dec;22(7):596-600. [9847011 ]
  3. Blanchard J, Weber CW, Shearer LE: Methylxanthine levels in breast milk of lactating women of different ethnic and socioeconomic classes. Biopharm Drug Dispos. 1992 Apr;13(3):187-96. [1576327 ]
  4. Sachse C, Ruschen S, Dettling M, Schley J, Bauer S, Muller-Oerlinghausen B, Roots I, Brockmoller J: Flavin monooxygenase 3 (FMO3) polymorphism in a white population: allele frequencies, mutation linkage, and functional effects on clozapine and caffeine metabolism. Clin Pharmacol Ther. 1999 Oct;66(4):431-8. [10546928 ]
  5. Desiraju RK, Sugita ET, Mayock RL: Determination of theophylline and its metabolites by liquid chromatography. J Chromatogr Sci. 1977 Dec;15(12):563-8. [591601 ]
  6. Tarka SM Jr, Arnaud MJ, Dvorchik BH, Vesell ES: Theobromine kinetics and metabolic disposition. Clin Pharmacol Ther. 1983 Oct;34(4):546-55. [6617078 ]
  7. Tserng KY, King KC, Takieddine FN: Theophylline metabolism in premature infants. Clin Pharmacol Ther. 1981 May;29(5):594-600. [7214789 ]
  8. Gonzalez-Jimenez J, Frutos G, Cayre I: Fluorescence quenching of human serum albumin by xanthines. Biochem Pharmacol. 1992 Aug 18;44(4):824-6. [1510729 ]
  9. Sommer KR, Hill RM, Horning MG: Identification and quantification of drugs in human amniotic fluid. Res Commun Chem Pathol Pharmacol. 1975 Nov;12(3):583-95. [1197933 ]
  10. Skopinska-Rozewska E, Janik P, Przybyszewska M, Sommer E, Bialas-Chromiec B: Inhibitory effect of theobromine on induction of angiogenesis and VEGF mRNA expression in v-raf transfectants of human urothelial cells HCV-29. Int J Mol Med. 1998 Dec;2(6):649-52. [9850731 ]
  11. Resman BH, Blumenthal P, Jusko WJ: Breast milk distribution of theobromine from chocolate. J Pediatr. 1977 Sep;91(3):477-80. [894424 ]
  12. Scott NR, Chakraborty J, Marks V: Determination of caffeine, theophylline and theobromine in serum and saliva using high-performance liquid chromatography. Ann Clin Biochem. 1984 Mar;21 ( Pt 2):120-4. [6712142 ]
  13. Emara S: Simultaneous determination of caffeine, theophylline and theobromine in human plasma by on-line solid-phase extraction coupled to reversed-phase chromatography. Biomed Chromatogr. 2004 Oct;18(8):479-85. [15386526 ]
  14. Gennaro MC, Abrigo C, Biglino P: Quantification of theophylline in human plasma by reversed-phase ion-interaction high-performance liquid chromatography and comparison with the TDx fluorescence polarization immunoassay procedure. Analyst. 1992 Jul;117(7):1071-4. [1524227 ]
  15. Slattery ML, West DW: Smoking, alcohol, coffee, tea, caffeine, and theobromine: risk of prostate cancer in Utah (United States). Cancer Causes Control. 1993 Nov;4(6):559-63. [8280834 ]
  16. Usmani OS, Belvisi MG, Patel HJ, Crispino N, Birrell MA, Korbonits M, Korbonits D, Barnes PJ: Theobromine inhibits sensory nerve activation and cough. FASEB J. 2005 Feb;19(2):231-3. Epub 2004 Nov 17. [15548587 ]

Enzymes

General function:
Involved in oxidoreductase activity
Specific function:
Key enzyme in purine degradation. Catalyzes the oxidation of hypoxanthine to xanthine. Catalyzes the oxidation of xanthine to uric acid. Contributes to the generation of reactive oxygen species. Has also low oxidase activity towards aldehydes (in vitro).
Gene Name:
XDH
Uniprot ID:
P47989
Molecular weight:
146422.99
Reactions
Theobromine + Water + Oxygen → 3,7-Dimethyluric acid + Hydrogen peroxidedetails
General function:
Involved in catalytic activity
Specific function:
Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes. May be involved in mediating central nervous system effects of therapeutic agents ranging from antidepressants to antiasthmatic and anti-inflammatory agents.
Gene Name:
PDE4B
Uniprot ID:
Q07343
Molecular weight:
64351.765
References
  1. Essayan DM: Cyclic nucleotide phosphodiesterases. J Allergy Clin Immunol. 2001 Nov;108(5):671-80. [11692087 ]
  2. Fisone G, Borgkvist A, Usiello A: Caffeine as a psychomotor stimulant: mechanism of action. Cell Mol Life Sci. 2004 Apr;61(7-8):857-72. [15095008 ]
  3. Daly JW: Caffeine analogs: biomedical impact. Cell Mol Life Sci. 2007 Aug;64(16):2153-69. [17514358 ]
  4. Deree J, Martins JO, Melbostad H, Loomis WH, Coimbra R: Insights into the regulation of TNF-alpha production in human mononuclear cells: the effects of non-specific phosphodiesterase inhibition. Clinics (Sao Paulo). 2008 Jun;63(3):321-8. [18568240 ]
General function:
Involved in monooxygenase activity
Specific function:
Metabolizes several precarcinogens, drugs, and solvents to reactive metabolites. Inactivates a number of drugs and xenobiotics and also bioactivates many xenobiotic substrates to their hepatotoxic or carcinogenic forms.
Gene Name:
CYP2E1
Uniprot ID:
P05181
Molecular weight:
56848.42
References
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. [19934256 ]
General function:
Involved in monooxygenase activity
Specific function:
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Most active in catalyzing 2-hydroxylation. Caffeine is metabolized primarily by cytochrome CYP1A2 in the liver through an initial N3-demethylation. Also acts in the metabolism of aflatoxin B1 and acetaminophen. Participates in the bioactivation of carcinogenic aromatic and heterocyclic amines. Catalizes the N-hydroxylation of heterocyclic amines and the O-deethylation of phenacetin.
Gene Name:
CYP1A2
Uniprot ID:
P05177
Molecular weight:
58406.915
References
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. [19934256 ]
  2. Gates S, Miners JO: Cytochrome P450 isoform selectivity in human hepatic theobromine metabolism. Br J Clin Pharmacol. 1999 Mar;47(3):299-305. [10215755 ]
General function:
Involved in G-protein coupled receptor protein signaling pathway
Specific function:
Receptor for adenosine. The activity of this receptor is mediated by G proteins which inhibit adenylyl cyclase
Gene Name:
ADORA1
Uniprot ID:
P30542
Molecular weight:
36511.3
References
  1. Chou CC, Vickroy TW: Antagonism of adenosine receptors by caffeine and caffeine metabolites in equine forebrain tissues. Am J Vet Res. 2003 Feb;64(2):216-24. [12602592 ]
  2. Gaytan SP, Saadani-Makki F, Bodineau L, Frugiere A, Larnicol N, Pasaro R: Effect of postnatal exposure to caffeine on the pattern of adenosine A1 receptor distribution in respiration-related nuclei of the rat brainstem. Auton Neurosci. 2006 Jun 30;126-127:339-46. Epub 2006 May 15. [16702031 ]
  3. Wang SJ: Caffeine facilitation of glutamate release from rat cerebral cortex nerve terminals (synaptosomes) through activation protein kinase C pathway: an interaction with presynaptic adenosine A1 receptors. Synapse. 2007 Jun;61(6):401-11. [17372967 ]
  4. Rieg T, Schnermann J, Vallon V: Adenosine A1 receptors determine effects of caffeine on total fluid intake but not caffeine appetite. Eur J Pharmacol. 2007 Jan 26;555(2-3):174-7. Epub 2006 Oct 25. [17126319 ]
  5. Mustafa S, Venkatesh P, Pasha K, Mullangi R, Srinivas NR: Altered intravenous pharmacokinetics of topotecan in rats with acute renal failure (ARF) induced by uranyl nitrate: do adenosine A1 antagonists (selective/non-selective) normalize the altered topotecan kinetics in ARF? Xenobiotica. 2006 Dec;36(12):1239-58. [17162470 ]
  6. Listos J, Malec D, Fidecka S: Adenosine receptor antagonists intensify the benzodiazepine withdrawal signs in mice. Pharmacol Rep. 2006 Sep-Oct;58(5):643-51. [17085856 ]
  7. Fisone G, Borgkvist A, Usiello A: Caffeine as a psychomotor stimulant: mechanism of action. Cell Mol Life Sci. 2004 Apr;61(7-8):857-72. [15095008 ]
  8. Daly JW, Jacobson KA, Ukena D: Adenosine receptors: development of selective agonists and antagonists. Prog Clin Biol Res. 1987;230:41-63. [3588607 ]
General function:
Involved in G-protein coupled receptor protein signaling pathway
Specific function:
Receptor for adenosine. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase
Gene Name:
ADORA2A
Uniprot ID:
P29274
Molecular weight:
44706.9
References
  1. Chou CC, Vickroy TW: Antagonism of adenosine receptors by caffeine and caffeine metabolites in equine forebrain tissues. Am J Vet Res. 2003 Feb;64(2):216-24. [12602592 ]
  2. Riksen NP, Franke B, van den Broek P, Smits P, Rongen GA: The 1976C>T polymorphism in the adenosine A2A receptor gene does not affect the vasodilator response to adenosine in humans in vivo. Pharmacogenet Genomics. 2007 Jul;17(7):551-4. [17558310 ]
  3. Zhao G, Messina E, Xu X, Ochoa M, Sun HL, Leung K, Shryock J, Belardinelli L, Hintze TH: Caffeine attenuates the duration of coronary vasodilation and changes in hemodynamics induced by regadenoson (CVT-3146), a novel adenosine A2A receptor agonist. J Cardiovasc Pharmacol. 2007 Jun;49(6):369-75. [17577101 ]
  4. Cornelis MC, El-Sohemy A, Campos H: Genetic polymorphism of the adenosine A2A receptor is associated with habitual caffeine consumption. Am J Clin Nutr. 2007 Jul;86(1):240-4. [17616786 ]
  5. Fisone G, Borgkvist A, Usiello A: Caffeine as a psychomotor stimulant: mechanism of action. Cell Mol Life Sci. 2004 Apr;61(7-8):857-72. [15095008 ]
  6. Daly JW, Jacobson KA, Ukena D: Adenosine receptors: development of selective agonists and antagonists. Prog Clin Biol Res. 1987;230:41-63. [3588607 ]