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How a ‘CYP of Coffee’ can help us to understand precision medicine

A few days back I met a friend in Cambridge city Centre and the delicious aroma of brewing coffee led us into a popular local café. The place was bustling with people, sitting around chatting and enjoying their coffees.

When our respective cuppas arrived, my friend announced: “You should drink your coffee black!” “I would if I could, but my CYPs are different to yours’’, I replied, somewhat defensively. ‘“Sip slow and you’ll get used to it”, she told me.

The ‘CYPs’ I’m referring to are the Cytochrome P450 enzymes that metabolize the caffeine in coffee, and I must admit to having something of a poor tolerance to caffeine.

Coffee

Coffee is the most popular drink in the world with over 400 billion cups consumed every year. Caffeine (1,3,7-trimethylxanthine) is a psychoactive substance that is metabolized by the enzyme Cytochrome P450 type1A2 (CYP1A2)1. In a study involving 40,000 individuals, this enzyme was found to determine caffeine intake.

Drug metabolism primarily occurs in the liver, where the lipid soluble compounds are converted to water-soluble compounds, facilitating detoxification and excretion. Cytochrome P450 enzymes are the prime catalysts in this process.

In the human species, there are more than 50 genes that encode for CYP enzymes. This results in inter-individual variability. There can be no doubt that Caffeine intake is associated with a range of physiologic effects, offering both detrimental and beneficial health outcomes. The CYPs are therefore important candidates when it comes to studying drug-drug interactions for use in personalized medicine.

The genetic polymorphism of cytochrome P450 enzymes can lead to individuals being extensive, intermediate, or poor metabolizers, which can result in variable drug responses, determining whether specific treatment is a success or failure.

For example, Codeine in cough medicine is metabolized to morphine via CYP2D6 that has analgesic and cough suppressant effect2. But, in individuals with gene duplication of CYP2D6, it can lead to 50% more morphine production, resulting in toxicity. The clinical significance of CYP-mediated drug interactions can be more significant when it comes to drugs with a narrow therapeutic window. CYP2D6 inhibition, for example, leads to decreased tamoxifen activity in breast cancer patients.

Drug-drug interactions occur as the result of a common drug metabolism pathway. The drugs can act as inhibitors, inducers, or substrates for a specific CYP enzymatic pathway. Drugs that inhibit an enzymatic pathway of CYP may cause increased concentrations of other drugs, which are metabolized by the same pathway, resulting in drug toxicity. Likewise, drugs that induce an enzymatic pathway of CYP may reduce concentrations of drugs that are metabolized by the same pathway, leading to sub-therapeutic drug levels or treatment failure.

A genome-wide association study (GWAS) on smoking behaviour found a strong association with the main nicotine metabolizing cytochrome P450, CYP2A6, the absence of which was associated with reduced levels of smoking3.

Stemnovate is developing a platform that will allow such drug interaction to be studied in the lab, allowing drugs to be tailored specifically to a patient’s needs, taking into account not only genomic variability but also physiological and lifestyle differences. Our ‘Liver on a chip’ project is being co-funded by Innovate UK. To find out more about it, please contact us at info@stemnovate.co.uk and we’ll be happy to talk about further…perhaps over a cup of coffee!

  1. Amin et al. Molecular Psychiatry (2012) 17, 1116–1129 doi:10.1038/mp.2011.101
  2. Leppert W, Pharmacology 2011;87:274–285 doi: 10.1159/000326085
  3. Siedlinski et al. Thorax. 2011;66 (10):894-902. doi:10.1136/thoraxjnl-2011-200154.