Pathway Caffeine Pathway, Pharmacokinetics

Stylized liver cell showing candidate genes involved in the metabolism of caffeine.
Caffeine Pathway, Pharmacokinetics
cyp1a2 cyp2e1 cyp1a2 cyp3a4 cyp2e1 cyp2c8 cyp2c9 cyp1a2 cyp2c9 cyp2c8 cyp3a4 cyp1a2 cyp1a2 cyp1a2 cyp2a6 nat2 xdh caffeine cyp2e1
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Caffeine is a naturally occurring stimulant found in coffee, tea, chocolate and used as an additive in other beverages and adjuvant analgesic in some pain medications [Articles:12204386, 20859801]. It is the most widely used drug in the world [Article:12397877]. Since its use is so widespread it can be hard to assess the effect of the drug in isolation and often pharmacogenomic associations have been studied based on intake of coffee or caffeinated beverages. These are also discussed here. Caffeine acts through multiple mechanisms, the most important of which is the antagonism of adenosine receptors (ADORA1 and ADORA2A) [Article:20859801]. Recent studies have suggested a role for caffeine in neuroprotection and as a potential treatment for Parkinson disease (PD) [Article:20182024].

Caffeine is almost completely metabolized with 3% or less being excreted unchanged in urine [Articles:17221922, 19211970]. The main route of metabolism in humans (70-80%) is via N-3 demethylation to paraxanthine also known as 1,7-dimethylxanthine or 17X [Articles:17221922, 19211970, 8529334]. This reaction is carried out by CYP1A2 in the liver [Article:17221922]. Experiments with human liver microsomes estimate that 1-N- demethylation to theobromine accounts for approximately 7 to 8% of caffeine metabolism with 7-N-demethylation to theophylline also around 7 to 8% [Article:18619574]. The remaining 15% of caffeine undergoes C-8 hydroxylation to form 1,3,7-trimethyluric acid [Article:18619574].

CYP1A2 is responsible for more than 95% of the primary metabolism of caffeine [Article:8491061]. Therefore caffeine is used as a probe drug for CYP1A2 activity with the relative ratios of urinary metabolites used as an indicator of the flux through different parts of the pathway [Article:17221922]. As well as paraxanthine, the major metabolites of caffeine in urine are 1-methylxanthine (1X), 1-methyluric acid (1U), 5-acetylamino-6-formylamino-3-methyluracil (AFMU), 1,7-dimethyluric acid (17U) [Article:17221922]. These are formed by the secondary metabolism of paraxanthine by CYP1A2, CYP2A6, NAT2 and XDH (also known as xanthine oxidase or XO) [Article:17221922]. In vitro studies in cell lines show involvement of CYP2E1 in the formation of theobromine and theophylline, whereas studies of recombinant proteins in microsomes do not support this but instead suggest that it contributes to the formation of 1,3,7-trimethyluric acid [Articles:1302044, 18619574]. Microsome experiments have shown that CYP2C8, CYP2C9 and CYP3A4 also participate in the primary metabolism of caffeine [Articles:19211970, 1302044, 18619574].

Caffeine has a half-life of 4 to 5 hours, which may be prolonged in patients with hepatic diseases, infants and neonates (up to 100 h), or during pregnancy [Article:17221922]. Smoking increases clearance of caffeine due to its actions on CYP1A2 [Article:15289794] (see below and CYP1A2 VIP).

The CYP1A2*1F allele is the most commonly studied variant with respect to caffeine. The variant that defines this haplotype is CYP1A2: (-163)C>A (rs762551). A study of CYP1A2*1F, where other haplotypes containing (-163)C>A were excluded, showed that (-163)AA was associated with increased metabolism of caffeine in Swedish smokers [Article:17370067] as well as in Swedish and Serbian heavy coffee consumers [Article:20390257]. Other haplotypes that included (-163)C>A (*1J, *1K, *21) did not have significantly altered metabolism of caffeine [Article:17370067]. However, another study of the CYP1A2*1K allele showed significantly reduced CYP1A2 activity in non-smokers compared to *1A or *1F, using caffeine as a probe substrate [Article:12920202]. For more details on CYP1A2 see CYP1A2 VIP.

Studies examining the effects of variants in the adenosine receptor ADORA2A and caffeine related behavior and responses have had mixed results. ADORA2A rs5751876 TT is associated with decreased habitual consumption of caffeine as compared to genotypes CC + CT and this association is more pronounced in smokers [Article:17616786]. ADORA2A rs5751876 TT, rs2298383 CC and rs4822492 CC were all associated with increased anxiety in response to caffeine in a healthy population that did not routinely consume much caffeine [Article:18305461]. The association with ADORA2A rs5751876 TT and increased caffeine-induced anxiety was also seen in a mostly white European non-smoking or light smoking population [Article:20520601]. However ADORA2A rs5751876 is not associated with vasodilator response when exposed to adenosine and caffeine [Article:17558310]. Conversely the CC genotype for ADORA2A rs5751876 is associated with increased likelihood of being sensitive to caffeine and increased likelihood of insomnia when exposed to caffeine. [Article:17329997].

Some studies have looked at the relationship between variants, caffeine and disease risk. Most have looked at Parkinson Disease (PD), a few studies have looked at cancer risk and one study investigated risk for cardiovascular events:

In the PEGASUS study of PD, CYP1A2 rs762551 genotype CC and rs2470890 CC is associated with decreased risk of Parkinson Disease in coffee drinkers [Article:21281405]. While two variants in ADORA2A were associated with reduced risk for PD there was no caffeine interaction noted in this study [Article:21281405]. None of the variants tested in ADORA2A (rs5751876 and rs3032740) or CYP1A2 (rs35694136 and rs762551) were associated with caffeine-related protection from PD in a study of people from the Midwest USA with mostly European ancestry [Article:18759349]. A study of Asians also failed to find any interaction between CYP1A2 rs762551, caffeine and PD although there was a significant association was seen between moderate to high caffeine intake and lower risk for PD [Article:18075470].

In a study of patients with breast cancer-predisposing BRCA1 variants, the C allele of rs762551 was associated with decreased risk for breast cancer in coffee drinkers compared to those who never consumed coffee [Article:17507615]. This protective effect of coffee was not seen in the rs762551 AA homozygotes [Article:17507615]. Studies of CYP1A2 and coffee consumption and risk for ovarian cancer [Article:18941913] or bladder cancer [Article:18798002] found no association. In vitro studies suggest the protective effects of caffeine against cancer may be by growth inhibition via PTEN and the PI3K/AKT pathway [Article:21617855].

In a study of South Americans, "slow" caffeine metabolizers, with the CYP1A2: (-163)C>A C allele, had increased risk of myocardial infarction [Article:16522833].

Authors: Caroline F. Thorn.
Thorn Caroline F, Aklillu Eleni, McDonagh Ellen M, Klein Teri E, Altman Russ B . "PharmGKB summary: caffeine pathway" Pharmacogenetics and genomics (2012).
Therapeutic Categories:
  • Pain, anti-inflammatory and immunomodulating agents
  • Neurological agents

Entities in the Pathway

Genes (8)

Drugs/Drug Classes (4)

Relationships in the Pathway

Arrow FromArrow ToControllersPMID
1,7-dimethylxanthine 1,7-dimethyluric acid CYP1A2, CYP2A6 17221922
1,7-dimethylxanthine 1-methyl xanthine
1,7-dimethylxanthine AFMU NAT2 17221922
1-methyl xanthine 1-methyluric acid XDH 17221922
caffeine 1,3,7-trimethyluric acid CYP1A2, CYP2C8, CYP2C9, CYP2E1, CYP3A4 19211970
caffeine 1,7-dimethylxanthine CYP1A2 17221922, 19211970, 8529334
caffeine theobromine CYP1A2, CYP2E1 1302044, 19211970
caffeine theophylline CYP1A2, CYP2C8, CYP2C9, CYP2E1, CYP3A4 1302044, 19211970
theophylline 1-methyl xanthine CYP1A2

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