Key takeaways:
- CYP2C8 is a phase I detoxification enzyme that breaks down several common medications and converts arachidonic acid into inflammatory and anti‑inflammatory lipid mediators.
- Variants in CYP2C8, such as CYP2C8*2, *3, and *4, can change how quickly you clear out drugs, such as ibuprofen, increasing your risk for GI bleeding from NSAIDs.
- Understanding your CYP genetic variants can help you understand your reaction to medications and guide conversations with your doctor.
This article is part of the Detoxification and Medication Genetic Lifehacks Hub.
Members will see their genotype report below and the solutions in the Lifehacks section. Consider joining today.CYP2C8: Metabolizing omega-6 fatty acids, ibuprofen, and more
The CYP450 (cytochrome 450) family of genes encodes enzymes that interact with prescription medications, hormones, toxins, and fatty acids. This family of enzymes includes CYP2C8, which is important in a process known as phase I detoxification, converting substances to be more easily excreted from the body. Genetic variants that alter how these enzymes work are responsible for varied individual responses to medications.
For example, differences in CYP2C8 activity can help explain why one person tolerates ibuprofen or certain diabetes medications, while another struggles with side effects.
CYP2C8 is an enzyme primarily found in the liver, as well as the intestines, kidneys, and brain. It breaks down, or metabolizes, about 5% of prescription medications as well as metabolizing polyunsaturated fatty acids (PUFA).
Let’s take a look first at the role CYP2C8 plays in breaking down polyunsaturated fats and then go into the medications and toxicants impacted by the gene.
CYP2C8 and PUFAs:
The CYP2C8 enzyme breaks down arachidonic acid into lipid metabolites that can have either pro- or anti-inflammatory effects.[ref]
Arachidonic acid is an omega-6 polyunsaturated fatty acid that we can get from certain foods or convert from linoleic acid (from soybean oil, corn oil, safflower oil, etc). Arachidonic acid and other polyunsaturated fatty acids can be converted in cells into bioactive molecules that signal for inflammation – or for the resolution of inflammation.[ref]
Related article: Specialized Pro-resolving Mediators (SPMs): The Resolution of Inflammation
CYP2C8, along with two other CYP genes, CYP2C9 and CYP2J2, catalyze the formation of epoxyeicosatrienoic acids (EETs) from arachidonic acid. EETs can be anti-inflammatory and help blood vessels to relax. However, they are short-lived and are broken down into pro-inflammatory molecules when overproduced.[ref] CYP2C8 can also form hydroxyeicosatetraenoic acids (HETEs) primarily in the lungs.[ref]
Eye health in aging:
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 interacted with omega-3 fatty acids, 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.
Medications metabolized by CYP2C8:
The CYP2C8 gene is essential in the metabolism of several chemotherapy drugs and plays a role in the metabolism of NSAIDs, such as ibuprofen.
Medications that are primarily metabolized by CYP2C8 include[ref]:
- Chloroquine
- Repaglinide
- Rosiglitazone
- Pioglitazone
- All-trans-retinoic acid
- Amiodarone
- Ibuprofen (along with CYP2C9)
- Tenoxicam (along with CYP2C9)
For people with genetic variants in CYP2C8 that decrease the function of the enzyme (see the genotype report below), a medication may remain in their system longer and could build up to a toxic amount.
Keep in mind that some medications can be metabolized using more than one CYP enzyme, so a decrease in CYP2C8 function may interact with other CYP variants in determining your reaction to medications. Talk with your doctor or pharmacist for help with prescription medications. They can help with understanding interactions with other genes and medications.
The ClinPGx database is a good source of information on pharmacological and genetic interactions. It has information on the CYP2C8 variants and response to tacrolimus, montelukast, rosiglitazone, and pioglitazone.
Natural supplements that interact with CYP2C8:
Natural supplements that you take can also interact with the CYP450 enzymes.
| Supplement | CYP2C8 effect | Practical implication if CYP2C8 is already slow | Key note for readers |
|---|---|---|---|
| Quercetin | Inhibitor of CYP2C8[ref] | May further slow metabolism of CYP2C8‑dependent drugs, increasing risk of side effects or higher drug levels | Consider timing or dose and talk with your doctor or pharmacist if you use quercetin with medications such as ibuprofen, repaglinide, or certain chemotherapies. |
| Pterostilbene | Inhibitor of CYP2C8[ref] | Similar to quercetin, could reduce CYP2C8 activity and slow drug clearance | Often paired with resveratrol; flag for readers who are on multiple medications or have reduced CYP2C8 function variants. |
| Trans‑resveratrol | Inhibitor of CYP2C8; can reduce pro‑inflammatory HETEs from arachidonic acid metabolism[ref] | May slow clearance of CYP2C8‑metabolized drugs, while potentially shifting arachidonic‑acid metabolites away from pro‑inflammatory pathways | Emphasize that any “detox” or anti‑inflammatory supplement can still change drug levels, so coordination with a clinician is important. |
| Luteolin | Inhibitor of CYP2C8[ref] | Could add to genetically reduced CYP2C8 function and prolong exposure to some medications | Many readers use luteolin for histamine or brain‑fog support; note the need to review medications before long‑term high‑dose use. |
| Diosmetin | Inhibitor of CYP2C8[ref] | May further decrease CYP2C8 activity, particularly relevant if combined with other inhibitors or decreased‑function variants | Common in some vein/vascular formulas; suggest checking labels and discussing with a healthcare provider when on chronic medications. |
Related articles: Quercetin: Scientific Studies + Genetic Connections
Luteolin: Antihistamine, Memory, and Brain Fog
CYP2C8 Genotype Report:
Your CYP2C8 genotype report below highlights whether you carry decreased‑ or increased‑function variants that can influence ibuprofen metabolism, NSAID bleeding risk, and eye‑health pathways.
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Lifehacks: What to avoid with CYP2C8 variants
Eye Health with a high PUFA diet:
Circling back 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 (arachidonic acid), especially if AMD (age macular degeneration) or diabetic retinopathy is a concern. Check out your genetic variants for age-related macular degeneration.
If you have the CYP2C8*3 variant and regularly take NSAIDs, you should talk with your doctor about the increased risk of gastrointestinal bleeding.
Check to see if you also have CYP2C9 variants:
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Related Articles and Topics:
Nrf2 Pathway: Increasing the Body’s Ability to Get Rid of Toxins
References: