Human Metabolome Database Version 3.5

Showing metabocard for Caffeine (HMDB01847)

Record Information
Version 3.5
Creation Date 2006-02-16 01:53:46 -0700
Update Date 2013-06-12 13:25:44 -0600
HMDB ID HMDB01847
Secondary Accession Numbers None
Metabolite Identification
Common Name Caffeine
Description Caffeine is the most widely consumed psychostimulant drug in the world that mostly is consumed in the form of coffee. Whether caffeine and/or coffee consumption contribute to the development of cardiovascular disease (CVD), the single leading cause of death in the US, is unclear. The literature indicates a strong relationship between boiled, unfiltered coffee consumption and elevated cholesterol levels; however, there is a critical gap in the literature regarding the effects of coffee or caffeine consumption on fibrinogen or CRP, which is an independent predictor of CVD risk. Available studies are limited by small samples sizes, inclusion of only men (or few women) and unrepresented age or ethnic groups. There is a critical need for controlled laboratory and epidemiological studies that include fibrinogen and CRP markers of CVD risk before conclusions can be drawn regarding the health effects of caffeine and/or coffee in a normal, healthy population of men and women. (PMID: 16856769 Link_out). The relationship between caffeine consumption and various illnesses such as cardiovascular disease and cancer remains equivocal. Prudence might dictate that pregnant women and chronically ill individuals exercise restraint in their use of caffeine, although research suggests relatively low or nonexistent levels of risk associated with moderate caffeine consumption. (PMID: 7844249 Link_out). There is extensive evidence that caffeine at dietary doses increases blood pressure (BP). However, concern that the drug may contribute to cardiovascular disease appears to have been dampened by (1) the belief that habitual use leads to the development of tolerance, and (2) confusion regarding relevant epidemiologic findings. When considered comprehensively, findings from experimental and epidemiologic studies converge to show that BP remains reactive to the pressor effects of caffeine in the diet. Overall, the impact of dietary caffeine on population BP levels is likely to be modest, probably in the region of 4/2 mm Hg. At these levels, however, population studies of BP indicate that caffeine use could account for premature deaths in the region of 14% for coronary heart disease and 20% for stroke. (PMID: 14747639 Link_out). Caffeine is a purine alkaloid that occurs naturally in coffee beans. At intake levels associated with coffee consumption, caffeine appears to exert most of its biological effects through the antagonism of the A1 and A2A subtypes of the adenosine receptor. Adenosine is an endogenous neuromodulator with mostly inhibitory effects, and adenosine antagonism by caffeine results in effects that are generally stimulatory. Some physiological effects associated with caffeine administration include central nervous system stimulation, acute elevation of blood pressure, increased metabolic rate, and diuresis. Caffeine is rapidly and almost completely absorbed in the stomach and small intestine and distributed to all tissues, including the brain. Caffeine metabolism occurs primarily in the liver, where the activity of the cytochrome P450 isoform CYP1A2 accounts for almost 95% of the primary metabolism of caffeine. CYP1A2-catalyzed 3-demethylation of caffeine results in the formation of 1,7-dimethylxanthine (paraxanthine). Paraxanthine may be demethylated by CYP1A2 to form 1-methylxanthine, which may be oxidized to 1-methyluric acid by xanthine oxidase. Paraxanthine may also be hydroxylated by CYP2A6 to form 1,7-dimethyluric acid, or acetylated by N-acetyltransferase 2 (NAT2) to form 5-acetylamino-6-formylamino-3-methyluracil, an unstable compound that may be deformylated nonenzymatically to form 5-acetylamino-6-amino-3-methyluracil. Caffeine concentrations in coffee beverages can be quite variable. A standard cup of coffee is often assumed to provide 100 mg of caffeine, but a recent analysis of 14 different specialty coffees purchased at coffee shops in the US found that the amount of caffeine in 8 oz (=240 ml) of brewed coffee ranged from 72 to 130 mg.Caffeine in espresso coffees ranged from 58 to 76 mg in a single shot. (PMID 16507475 Link_out). Caffeine is a member of the methylxanthine family of drugs, and is the most widely consumed behaviourally active substance in the western world. A number of in vitro and in vivo studies have demonstrated that caffeine modulates both innate and adaptive immune responses. For instance studies indicate that caffeine and its major metabolite paraxanthine suppress neutrophil and monocyte chemotaxis, and also suppress production of the pro-inflammatory cytokine tumor necrosis factor (TNF) alpha from human blood. Caffeine has also been reported to suppress human lymphocyte function as indicated by reduced T-cell proliferation and impaired production of Th1 (interleukin [IL]-2 and interferon [IFN]-gamma), Th2 (IL-4, IL-5) and Th3 (IL-10) cytokines. Studies also indicate that caffeine suppresses antibody production. The evidence suggests that at least some of the immunomodulatory actions of caffeine are mediated via inhibition of cyclic adenosine monophosphate (cAMP)-phosphodiesterase (PDE), and consequential increase in intracellular cAMP concentrations. Overall, these studies indicate that caffeine, like other members of the methylxanthine family, is largely anti-inflammatory in nature, and based on the pharmacokinetics of caffeine, many of its immunomodulatory effects occur at concentrations that are relevant to normal human consumption. (PMID 16540173 Link_out).
Structure Thumb
Download: MOL | SDF | PDB | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
  1. 1,3,7-Trimethyl-2,6-dioxopurine
  2. 1,3,7-Trimethyl-3,7-dihydro-1H-purine-2,6-dione
  3. 1,3,7-Trimethylxanthine
  4. 1-Methyl-Theobromine
  5. 3,7-Dihydro-1,3,7-trimethyl-1H-purine-2,6-dione
  6. 7-Methyl Theophylline
  7. Anhydrous caffeine (JP15)
  8. Guaranine
  9. Hycomine
  10. Lanorinal
  11. Methyltheobromide
  12. Methylxanthine theophylline
  13. Monohydrate Caffeine
  14. Propoxyphene
  15. Thein
Chemical Formula C8H10N4O2
Average Molecular Weight 194.1906
Monoisotopic Molecular Weight 194.080375584
IUPAC Name 1,3,7-trimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione
Traditional IUPAC Name caffeine
CAS Registry Number 58-08-2
SMILES CN1C=NC2=C1C(=O)N(C)C(=O)N2C
InChI Identifier InChI=1S/C8H10N4O2/c1-10-4-9-6-5(10)7(13)12(3)8(14)11(6)2/h4H,1-3H3
InChI Key RYYVLZVUVIJVGH-UHFFFAOYSA-N
Chemical Taxonomy
Kingdom Organic Compounds
Super Class Aromatic Heteropolycyclic Compounds
Class Imidazopyrimidines
Sub Class Purines and Purine Derivatives
Other Descriptors
  • Organic Compounds
  • Purine alkaloids(KEGG)
  • Purinones
  • a small molecule(Cyc)
  • trimethylxanthine(ChEBI)
Substituents
  • Imidazole
  • Pyrimidine
  • Pyrimidone
Direct Parent Xanthines
Ontology
Status Detected and Quantified
Origin
  • Drug
  • Drug metabolite
  • Food
Biofunction
  • Waste products
Application Not Available
Cellular locations
  • Cytoplasm (predicted from logP)
Physical Properties
State Solid
Experimental Properties
Property Value Reference
Melting Point 238 °C Not Available
Boiling Point Not Available Not Available
Water Solubility 21.6 mg/mL at 25 °C Not Available
LogP -0.07 HANSCH,C ET AL. (1995)
Predicted Properties
Property Value Source
LogP -0.24 ALOGPS
LogP -0.55 ChemAxon
LogS -1.25 ALOGPS
pKa (strongest basic) -0.92 ChemAxon
Hydrogen Acceptor Count 3 ChemAxon
Hydrogen Donor Count 0 ChemAxon
Polar Surface Area 58.44 A2 ChemAxon
Rotatable Bond Count 0 ChemAxon
Refractivity 49.83 ChemAxon
Polarizability 18.96 ChemAxon
Formal Charge 0 ChemAxon
Physiological Charge 0 ChemAxon
Spectra
Gas-MS Spectrum
1H NMR Spectrum
MS/MS Spectrum Quattro_QQQ 10
MS/MS Spectrum Quattro_QQQ 25
MS/MS Spectrum Quattro_QQQ 40
MS/MS Spectrum EI-B (HITACHI M-80)
MS/MS Spectrum CI-B (Unknown)
MS/MS Spectrum EI-B (HITACHI M-60)
MS/MS Spectrum EI-B (HITACHI M-68)
MS/MS Spectrum CI-B (HITACHI M-60)
MS/MS Spectrum LC-ESI-QQ (API3000, Applied Biosystems) 10
MS/MS Spectrum LC-ESI-QQ (API3000, Applied Biosystems) 20
MS/MS Spectrum LC-ESI-QQ (API3000, Applied Biosystems) 30
MS/MS Spectrum LC-ESI-QQ (API3000, Applied Biosystems) 40
MS/MS Spectrum LC-ESI-QQ (API3000, Applied Biosystems) 50
MS/MS Spectrum GC-EI-TOF (Pegasus III TOF-MS system, Leco; GC 6890, Agilent Technologies)
MS/MS Spectrum GC-EI-TOF (Pegasus III TOF-MS system, Leco; GC 6890, Agilent Technologies)
[1H,1H] 2D NMR Spectrum
[1H,13C] 2D NMR Spectrum
Biological Properties
Cellular Locations
  • Cytoplasm (predicted from logP)
Biofluid Locations
  • Blood
  • Cerebrospinal Fluid (CSF)
  • Urine
Tissue Location
  • Kidney
  • Liver
  • Prostate
  • Skin
Pathways
Name SMPDB Link KEGG Link
Caffeine Metabolism SMP00028 map00232 Link_out
Normal Concentrations
Biofluid Status Value Age Sex Condition Reference
Blood Detected and Quantified
78.0 (26.0-129.0) uM Adult (>18 years old) Both Normal
  • McPherson, R...
  • Louise M. M...
Urine Detected but not Quantified
Not Applicable Adult (>18 years old) Both Normal
Urine Detected and Quantified
0.33 (0.0-1.01) umol/mmol creatinine Adult (>18 years old) Both Normal
Urine Detected and Quantified
1.2 umol/mmol creatinine Adult (>18 years old) Both Comment Normal
Abnormal Concentrations
Biofluid Status Value Age Sex Condition Reference
Cerebrospinal Fluid (CSF) Detected and Quantified 1.139 +/- 0.407 uM Adult (>18 years old) Both Traumatic Brain Injury (TBI)
Urine Detected and Quantified 0.5 (0.0-1.35) umol/mmol creatinine Adult (>18 years old) Both Comment Asthma
Associated Disorders and Diseases
Disease References
Asthma
  • 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. Pubmed: 15537072 Link_out
      Associated OMIM IDs
      DrugBank ID DB00201 Link_out
      DrugBank Metabolite ID DBMET00535 Link_out
      Phenol Explorer Compound ID Not Available
      Phenol Explorer Metabolite ID Not Available
      FoodDB ID FDB002100
      KNApSAcK ID C00001492 Link_out
      Chemspider ID 2424 Link_out
      KEGG Compound ID C07481 Link_out
      BioCyc ID Not Available
      BiGG ID Not Available
      Wikipedia Link Caffeine Link_out
      NuGOwiki Link HMDB01847 Link_out
      Metagene Link HMDB01847 Link_out
      METLIN ID 1455 Link_out
      PubChem Compound 2519 Link_out
      PDB ID CFF Link_out
      ChEBI ID 27732 Link_out
      References
      Synthesis Reference Not Available
      Material Safety Data Sheet (MSDS) Download (PDF)
      General References
      1. Miyake Y, Sakaguchi K, Iwasaki Y, Ikeda H, Makino Y, Kobashi H, Araki Y, Ando M, Kita K, Shiratori Y: New prognostic scoring model for liver transplantation in patients with non-acetaminophen-related fulminant hepatic failure. Transplantation. 2005 Oct 15;80(7):930-6. Pubmed: 16249741 Link_out
      2. Wilkinson SC, Maas WJ, Nielsen JB, Greaves LC, van de Sandt JJ, Williams FM: Interactions of skin thickness and physicochemical properties of test compounds in percutaneous penetration studies. Int Arch Occup Environ Health. 2006 May;79(5):405-13. Epub 2006 Jan 25. Pubmed: 16435152 Link_out
      3. Spiller HA, Winter ML, Klein-Schwartz W, Bangh SA: Efficacy of activated charcoal administered more than four hours after acetaminophen overdose. J Emerg Med. 2006 Jan;30(1):1-5. Pubmed: 16434328 Link_out
      4. Ayotte P, Dewailly E, Lambert GH, Perkins SL, Poon R, Feeley M, Larochelle C, Pereg D: Biomarker measurements in a coastal fish-eating population environmentally exposed to organochlorines. Environ Health Perspect. 2005 Oct;113(10):1318-24. Pubmed: 16203240 Link_out
      5. Shah S, Budev M, Blazey H, Fairbanks K, Mehta A: Hepatic veno-occlusive disease due to tacrolimus in a single-lung transplant patient. Eur Respir J. 2006 May;27(5):1066-8. Pubmed: 16707401 Link_out
      6. Larson AM, Polson J, Fontana RJ, Davern TJ, Lalani E, Hynan LS, Reisch JS, Schiodt FV, Ostapowicz G, Shakil AO, Lee WM: Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. Hepatology. 2005 Dec;42(6):1364-72. Pubmed: 16317692 Link_out
      7. Septer S, Thompson ES, Willemsen-Dunlap A: Anesthesia concerns for children with tuberous sclerosis. AANA J. 2006 Jun;74(3):219-25. Pubmed: 16786916 Link_out
      8. Sreekumar A, Poisson LM, Rajendiran TM, Khan AP, Cao Q, Yu J, Laxman B, Mehra R, Lonigro RJ, Li Y, Nyati MK, Ahsan A, Kalyana-Sundaram S, Han B, Cao X, Byun J, Omenn GS, Ghosh D, Pennathur S, Alexander DC, Berger A, Shuster JR, Wei JT, Varambally S, Beecher C, Chinnaiyan AM: Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression. Nature. 2009 Feb 12;457(7231):910-4. Pubmed: 19212411 Link_out
      9. Rodrigues IM, Klein LC: Boiled or filtered coffee? Effects of coffee and caffeine on cholesterol, fibrinogen and C-reactive protein. Toxicol Rev. 2006;25(1):55-69. Pubmed: 16856769 Link_out
      10. Lamarine RJ: Selected health and behavioral effects related to the use of caffeine. J Community Health. 1994 Dec;19(6):449-66. Pubmed: 7844249 Link_out
      11. James JE: Critical review of dietary caffeine and blood pressure: a relationship that should be taken more seriously. Psychosom Med. 2004 Jan-Feb;66(1):63-71. Pubmed: 14747639 Link_out
      12. Higdon JV, Frei B: Coffee and health: a review of recent human research. Crit Rev Food Sci Nutr. 2006;46(2):101-23. Pubmed: 16507475 Link_out
      13. Horrigan LA, Kelly JP, Connor TJ: Immunomodulatory effects of caffeine: friend or foe? Pharmacol Ther. 2006 Sep;111(3):877-92. Epub 2006 Mar 15. Pubmed: 16540173 Link_out
      14. Nehlig A, Daval JL, Debry G: Caffeine and the central nervous system: mechanisms of action, biochemical, metabolic and psychostimulant effects. Brain Res Brain Res Rev. 1992 May-Aug;17(2):139-70. Pubmed: 1356551 Link_out
      15. Benjamin LT Jr, Rogers AM, Rosenbaum A: Coca-Cola, caffeine, and mental deficiency: Harry Hollingworth and the Chattanooga trial of 1911. J Hist Behav Sci. 1991 Jan;27(1):42-55. Pubmed: 2010614 Link_out
      16. Nathanson JA: Caffeine and related methylxanthines: possible naturally occurring pesticides. Science. 1984 Oct 12;226(4671):184-7. Pubmed: 6207592 Link_out
      17. Smit HJ, Gaffan EA, Rogers PJ: Methylxanthines are the psycho-pharmacologically active constituents of chocolate. Psychopharmacology (Berl). 2004 Nov;176(3-4):412-9. Epub 2004 May 5. Pubmed: 15549276 Link_out
      18. Haskell CF, Kennedy DO, Wesnes KA, Milne AL, Scholey AB: A double-blind, placebo-controlled, multi-dose evaluation of the acute behavioural effects of guarana in humans. J Psychopharmacol. 2007 Jan;21(1):65-70. Epub 2006 Mar 13. Pubmed: 16533867 Link_out

      Enzymes
      Name: cAMP-specific 3',5'-cyclic phosphodiesterase 4B
      Reactions: Not Available
      Gene Name: PDE4B
      Uniprot ID: Q07343 Link_out
      Protein Sequence: FASTA
      Gene Sequence: FASTA
      Name: Cytochrome P450 3A4
      Reactions: Not Available
      Gene Name: CYP3A4
      Uniprot ID: P08684 Link_out
      Protein Sequence: FASTA
      Gene Sequence: FASTA
      Name: Cytochrome P450 2C9
      Reactions: Not Available
      Gene Name: CYP2C9
      Uniprot ID: P11712 Link_out
      Protein Sequence: FASTA
      Gene Sequence: FASTA
      Name: Cytochrome P450 2C19
      Reactions: Not Available
      Gene Name: CYP2C19
      Uniprot ID: P33261 Link_out
      Protein Sequence: FASTA
      Gene Sequence: FASTA
      Name: Cytochrome P450 2E1
      Reactions: Not Available
      Gene Name: CYP2E1
      Uniprot ID: P05181 Link_out
      Protein Sequence: FASTA
      Gene Sequence: FASTA
      Name: Cytochrome P450 3A43
      Reactions: Not Available
      Gene Name: CYP3A43
      Uniprot ID: Q9HB55 Link_out
      Protein Sequence: FASTA
      Gene Sequence: FASTA
      Name: Cytochrome P450 1B1
      Reactions: Not Available
      Gene Name: CYP1B1
      Uniprot ID: Q16678 Link_out
      Protein Sequence: FASTA
      Gene Sequence: FASTA
      Name: Cytochrome P450 2D6
      Reactions: Not Available
      Gene Name: CYP2D6
      Uniprot ID: P10635 Link_out
      Protein Sequence: FASTA
      Gene Sequence: FASTA
      Name: Cytochrome P450 2C18
      Reactions: Not Available
      Gene Name: CYP2C18
      Uniprot ID: P33260 Link_out
      Protein Sequence: FASTA
      Gene Sequence: FASTA
      Name: Cytochrome P450 2F1
      Reactions: Not Available
      Gene Name: CYP2F1
      Uniprot ID: P24903 Link_out
      Protein Sequence: FASTA
      Gene Sequence: FASTA
      Name: Cytochrome P450 4X1
      Reactions: Not Available
      Gene Name: CYP4X1
      Uniprot ID: Q8N118 Link_out
      Protein Sequence: FASTA
      Gene Sequence: FASTA
      Name: Cytochrome P450 2B6
      Reactions: Not Available
      Gene Name: CYP2B6
      Uniprot ID: P20813 Link_out
      Protein Sequence: FASTA
      Gene Sequence: FASTA
      Name: Cytochrome P450 3A5
      Reactions: Not Available
      Gene Name: CYP3A5
      Uniprot ID: P20815 Link_out
      Protein Sequence: FASTA
      Gene Sequence: FASTA
      Name: Cytochrome P450 1A1
      Reactions: Not Available
      Gene Name: CYP1A1
      Uniprot ID: P04798 Link_out
      Protein Sequence: FASTA
      Gene Sequence: FASTA
      Name: Cytochrome P450 2A13
      Reactions: Not Available
      Gene Name: CYP2A13
      Uniprot ID: Q16696 Link_out
      Protein Sequence: FASTA
      Gene Sequence: FASTA
      Name: Cytochrome P450 3A7
      Reactions: Not Available
      Gene Name: CYP3A7
      Uniprot ID: P24462 Link_out
      Protein Sequence: FASTA
      Gene Sequence: FASTA
      Name: Cytochrome P450 4B1
      Reactions: Not Available
      Gene Name: CYP4B1
      Uniprot ID: P13584 Link_out
      Protein Sequence: FASTA
      Gene Sequence: FASTA
      Name: Cytochrome P450 4Z1
      Reactions: Not Available
      Gene Name: CYP4Z1
      Uniprot ID: Q86W10 Link_out
      Protein Sequence: FASTA
      Gene Sequence: FASTA
      Name: Cytochrome P450 1A2
      Reactions: Not Available
      Gene Name: CYP1A2
      Uniprot ID: P05177 Link_out
      Protein Sequence: FASTA
      Gene Sequence: FASTA
      Name: Cytochrome P450 19A1
      Reactions: Not Available
      Gene Name: CYP19A1
      Uniprot ID: P11511 Link_out
      Protein Sequence: FASTA
      Gene Sequence: FASTA
      Name: Cytochrome P450 2C8
      Reactions: Not Available
      Gene Name: CYP2C8
      Uniprot ID: P10632 Link_out
      Protein Sequence: FASTA
      Gene Sequence: FASTA
      Name: Cytochrome P450 2S1
      Reactions: Not Available
      Gene Name: CYP2S1
      Uniprot ID: Q96SQ9 Link_out
      Protein Sequence: FASTA
      Gene Sequence: FASTA
      Name: Cytochrome P450 2J2
      Reactions: Not Available
      Gene Name: CYP2J2
      Uniprot ID: P51589 Link_out
      Protein Sequence: FASTA
      Gene Sequence: FASTA
      Name: Cytochrome P450 2A7
      Reactions: Not Available
      Gene Name: CYP2A7
      Uniprot ID: P20853 Link_out
      Protein Sequence: FASTA
      Gene Sequence: FASTA
      Name: Cytochrome P450 2A6
      Reactions: Not Available
      Gene Name: CYP2A6
      Uniprot ID: P11509 Link_out
      Protein Sequence: FASTA
      Gene Sequence: FASTA
      Name: Adenosine receptor A1
      Reactions: Not Available
      Gene Name: ADORA1
      Uniprot ID: P30542 Link_out
      Protein Sequence: FASTA
      Gene Sequence: FASTA
      Name: Adenosine receptor A2a
      Reactions: Not Available
      Gene Name: ADORA2A
      Uniprot ID: P29274 Link_out
      Protein Sequence: FASTA
      Gene Sequence: FASTA
      Name: Cytochrome P450, family 1, subfamily A, polypeptide 1
      Reactions: Not Available
      Gene Name: CYP1A1
      Uniprot ID: A0N0X8 Link_out
      Protein Sequence: FASTA
      Gene Sequence: FASTA
      Name: Ryanodine receptor 1
      Reactions: Not Available
      Gene Name: RYR1
      Uniprot ID: P21817 Link_out
      Protein Sequence: FASTA
      Gene Sequence: FASTA
      Name: Cytochrome P450 2D6
      Reactions: Not Available
      Gene Name: CYP2D6
      Uniprot ID: Q6NWU0 Link_out
      Protein Sequence: FASTA
      Gene Sequence: FASTA
      Transporters
      Name: Multidrug resistance protein 1
      Reactions: Not Available
      Gene Name: ABCB1
      Uniprot ID: P08183 Link_out
      Protein Sequence: FASTA
      Gene Sequence: FASTA