CYP2C9 Genetic Variants and Drug Metabolism

Have you ever wondered why certain medications don’t work well for you? Genetic variants can change how fast or how slow a medication, toxicant, or supplement is broken down and eliminated by your body.

The CYP2C9 gene is part of the CYP450 family of genes, which code for the enzymes needed for phase I detoxification. (Learn more about other phase I detoxification genes.)

CYP2C9: Breaking down prescription medications and more

The CYP2C9 gene that codes for an enzyme that metabolizes, or breaks down, quite a few medications in the liver.

CYP2C9 also breaks down linoleic acid, arachidonic acid, and serotonin outside of the liver.[ref]

Some popular prescription medications metabolized by using the CYP2C9 enzyme include:

  • losartan (blood pressure)
  • warfarin (Coumadin)
  • acenocoumarol
  • tolbutamide (Orinase)
  • glipizide (Glucotrol)
  • ibuprofen (Advil, Motrin)
  • celecoxib (Celebrex)
  • montelukast (Singulair)
  • naproxen (Aleve).
  • A complete list can be found on Pharmacy Times.

There are several genetic variants of CYP2C9  that either increase or decrease the activity level of the enzyme.

This is important when looking at how your body is going to respond to different doses of common drugs.

Let’s look at some examples of how the CYP2C9 variants are important:

  • With some loss-of-function variants of CYP2C9, people may have an increased risk of stomach bleeding with NSAIDs.[ref]
  • Celecoxib (Celebrex), a popular medication, is metabolized by the CYP2C9 enzyme. A new study recommends a lower starting dosage for those with reduced enzyme function.[ref]
  • Warfarin is a popular prescription anticoagulant, often used after strokes or for those at risk for blood clots.  Dosage variations that are determined by genetic factors are mainly based on the CYP2C9 and VKORC1 gene variants.
  • A popularly prescribed statin, Crestor (rosuvastatin), is also partially metabolized by CYP2C9.  A recent study found that those with slow CYP2C9 variants had more of a reduction of LDL levels when using rosuvastatin.[ref]
  • THC, the active component of cannabis, is partially metabolized by CYP2C9.[ref]

What should you do if you are a slow or fast CYP2C9 metabolizer?

Knowing how your body metabolizes different medications is important. But it is not as simple as just taking more of a medication if you are a slow metabolizer.

A lot of medications can be metabolized by using several different CYP enzymes, so your body may have a good backup route for breaking down some drugs and toxins. For example, the sleep medication Ambien is metabolized through several different CYP enzymes including CYP2C9. But research shows the slow CYP2C9 enzymes only matter for people who also have inhibited CYP3A4. [ref]

Some medications need to be metabolized using a CYP enzyme before they will begin to work because the metabolite is actually the drug. This type of medication is called a pro-drug since the actionable drug is actually formed by your body breaking down the pro-drug.

For other medications, the tablet you take is the actual drug and the speed at which it is broken down affects how long it stays in your system.

This gets complicated (talk with your doctor):

Knowing whether you are a slow metabolizer or a fast metabolizer is only part of the picture. You also need to know how the drug works as well as whether there are any interactions with other medications. This is one of those ‘talks’ with your doctor or pharmacist situations if you are taking several prescription medication.

To add one more layer of complexity here, most of the studies on drug metabolism use adult study participants. In children, some medications metabolize slightly differently.  For example, valproate, an epilepsy medication,  mainly uses CYP2C9 in children for metabolization but not in adults.[ref]


CYP2C9 Genetic Variants:

Variants in the CYP2C9 gene impact the way many medications work and may alter the amount of a medication you need to take.

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There are more than 50 variants of CYP2C9 that impact how the enzyme functions.  Below are just a few of the more common variants — the ones that are available in 23andMe or AncestryDNA raw data…

Check your genetic data for rs1799853 (23andMe v4, v5):

  •  T/T: CYP2C9*2 – poor metabolizer; 40% reduction in Warfarin metabolism[study]
  • C/T:  One copy of CYP2C9*2, reduced activity
  •  C/C: typical

Members: Your genotype for rs1799853 is .

 

Check your genetic data for rs1057910 (23andMe v4, v5; AncestryDNA):

  • C/C: CYP2C9*3 – poor metabolizer; 80% reduction in Warfarin metabolism[study] slower metabolism of THC (cannabis)[ref]
  • A/C:  One copy of CYP2C9*3, reduced activity; 40% reduction in Warfarin metabolism
  •  A/A: typical

Members: Your genotype for rs1057910 is .

 

Check your genetic data for rs2256871 (23andMe v4, v5; AncestryDNA):

  • G/G: CYP2C9*9 – poor metabolizer[ref][ref]
  • A/G:  One copy of CYP2C9*9, decreased metabolism
  •  A/A: typical

Members: Your genotype for rs2256871 is .

 

Check your genetic data for rs9332131 (23andMe v4, v5):

  •  – – or DD: CYP2C9*6 – poor metabolizer[ref]
  • A/A: typical

Members: Your genotype for rs9332131 is .

 

Check your genetic data for rs28371685 (23andMe v4, v5; AncestryDNA):

  • T/T: CYP2C9*11 – poor metabolizer[study]
  • C/T: One CYP2C9*11 allele, reduced activity
  • C/C: typical

Members: Your genotype for rs28371685 is .

 


Lifehacks:

Talk with your doctor or pharmacists if you have questions about specific prescription medications.

Check CYP2C8: For some medication, another CYP enzyme may be able to also metabolize the drug.  In the case of NSAIDs and CYP2C9, the backup route of metabolism is CYP2C8. People with slow CYP2C8 and slow CYP2C9 are at a significantly increased risk of side effects from NSAIDs. If you have a genetic variant that slows the CYP2C9 enzyme, please also check your CYP2C8 variants.

Short-term fasting may reduce CYP2C9 activity; a 36 hour fast reduced CYP2C9 activity by 19%.  Keep this in mind if you are taking a medication metabolized by CYP2C9, this can affect how long the medication is active for you.  For example, this could affect your clot time if you are taking Warfarin while fasting.[ref]

Hesperidin, a flavonoid found in lemons and oranges, is an inhibitor of CYP2C9.[ref] (Read more about hesperidin)

High doses of Quercetin interacts with warfarin dosages, but not through CYP2C9 metabolism.  “Quercetin metabolites are able to strongly displace warfarin from HSA suggesting that high quercetin doses can strongly interfere with warfarin therapy. On the other hand, tested flavonoids showed no or weaker inhibition of CYP2C9 compared to warfarin, making it very unlikely that quercetin or its metabolites can significantly inhibit the CYP2C9-mediated inactivation of warfarin.”[ref]  (Read more about quercetin)


Related Genes and Topics:

CYP2D6: Variants that cause reactions to common medications
CYP2D6 is responsible for the break down and elimination of about 25% of prescription medications. Genetic variants in CYP2D6 can significantly impact the way that you react to certain drugs.

Nrf2 Pathway: Increasing the body’s ability to get rid of toxins
The Nrf2 (Nuclear factor erythroid 2–related factor) signaling pathway regulates the expression of antioxidants and phase II detoxification enzymes. This is a fundamental pathway that is important in how well your body functions.

Phase I and Phase II detoxification
Learn how the different genetic variants in the phase I and phase II detoxification genes impact the way that you react to medications and break down different toxins.




Author Information:   Debbie Moon
Debbie Moon is the founder of Genetic Lifehacks. She holds a Master of Science in Biological Sciences from Clemson University and an undergraduate degree in engineering from Colorado School of Mines. Debbie is a science communicator who is passionate about explaining evidence-based health information. Her goal with Genetic Lifehacks is to bridge the gap between the research hidden in scientific journals and everyone's ability to use that information. To contact Debbie, visit the contact page.