CYP2C8: Prescription medications and arachidonic acid

The CYP (cytochrome) family of genes codes for a number of different enzymes that interact with prescription drugs. This family of enzymes is important in breaking down medications in a process known as phase I detoxification. Genetic variants that alter the way that these enzymes work can impact your reaction to a medication.

The CYP2C8 gene is important in the metabolism of several chemotherapy drugs (e.g. Taxol) as well as playing a role in the metabolism of NSAIDs.

Here is a good list of drugs metabolized using CYP2C8 along with the other enzymes that can also play a role in their metabolism.  A database of pharmacological and genetic interactions has information on the CYP2C8 variants and response to tacrolimus, montelukast, rosiglitazone, and pioglitazone. More information can also be found in this publication.

In addition pharmaceutical drugs, CYP2C8 also metabolizes arachidonic acid in the body, which is important in blood pressure regulation. This may also be important in oxidative stress in the cell. [ref ]

The metabolism of arachidonic acid by CYP2C8 is also important in eye health in aging. Hypoxia, or low oxygen, increases CYP2C8, which in turn causes more of the conversion of arachidonic acid into epoxyeicosatrienoic acids (EETs). The increased EETs then promote abnormal vascular development in the retina of the eye. Additionally, the increased CYP2C8 also interacted with omega-3 fatty acids, also promoting abnormal vascular development with higher levels of DHA in low oxygen conditions. [ref ]

Inhibiting CYP2C8 has been shown in studies to decrease the pathological effects in the eye from increased vascular development. This could be important in age-related macular degeneration and diabetic retinopathy. [ref ]  Please keep in mind that you don’t want to inhibit CYP2C8 if you are on a prescription medication that relies on the enzyme.


Genetic Variants in CYP2C8:

There are genetic variants that occur in the CYP2C8 gene that impact how the enzyme functions.

Check your genetic data for rs10509681 (23andMe v4, v5; AncestryDNA):

  • C/C: CYP2C8*3, decreased enzyme function[ref ]; ibuprofen takes longer to be metabolized [ref ]; increased risk of GI bleeding with NSAIDs [ref ], increased risk of neuropathy in breast cancer patients treated with paclitaxel[ref ]
  • C/T: one copy of CYP2C8*3, decreased enzyme function; increased risk of GI bleeding with NSAIDs
  • T/T: normal

Check your genetic data for rs11572103 (23andMe v4, v5; AncestryDNA):

  • A/A: CYP2C8*2; decreased enzyme function[ref ]
  • A/T: one copy of CYP2C8*2; decreased enzyme function[ref ]
  • T/T: normal

Check your genetic data for rs1058930 (23andme v4, v5; AncestryDNA):

  • C/C: CYP2C8*4; slightly decreased enzyme function[ref]
  • C/G: one copy of CYP2C8*4; slightly decreased enzyme function
  • G/G: normal

Check your genetic data for rs7909236 (23andMe v4; AncestryDNA):

  • T/T: CYP2C8*1B; increased enzyme activity [ref] increased risk of hypertension[ref ]
  • G/T: one copy of CYP2C8*1B; increased enzyme activity [ref]
  • G/G: normal

Lifehacks:

If you carry the CYP2C8*3 variant and take a lot of NSAIDs, you should seriously talk with your doctor about the increased risk of GI bleeds.

Quercetin, a flavonoid that is often used as an anti-inflammatory supplement, is an inhibitor of CYP2C8.[ref ] If you carry a genetic variant that slows CYP2C8 plus take quercetin along with a medication that uses CYP2C8, the interaction could cause the medication not to work appropriately.

Circling back around to the information above on how upregulation of CYP2C8 could increase problems with the retina, such as macular degeneration or diabetic retinopathy…  Quercetin, an inhibitor of CYP2C8, has been shown to protect the eye from damage from diabetic retinopathy in animal studies. [ref ]  This may be something to consider if on a diet that is high in the long-chain omega-6 or omega-3 fatty acids, especially if AMD or diabetic retinopathy is a concern.

More to read:
Check out your other CYP450 genetic variants: Phase I and Phase II Detoxification

 



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. 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.