CYP2C8 is one of the most important drug-metabolizing detox enzymes. It processes over 60 clinical drugs including antidiabetics (rosiglitazone), anticancer drugs (paclitaxel, imatinib), and NSAIDs (diclofenac, ibuprofen). Find out how gene variants may affect you in terms of drug response, and which supplements/drugs interfere with CYP2C8 activity.
What is CYP2C8?
CYP2C8 is one of the cytochrome P450 monooxygenases (CYPs). These are enzymes that eliminate most of the drugs and toxins from the human body [1].
CYP2C8 Function
This enzyme metabolizes over 60 clinical drugs [2], including:
- Antidiabetic drugs: rosiglitazone, thiazolidinedione, meglitinide, repaglinide, troglitazone and pioglitazone [3, 4, 5, 6].
- Anticancer drugs: paclitaxel and cabazitaxel [3].
- Chemotherapeutics: taxanes and imatinib [4].
- Cholesterol-lowering cerivastatin and fluvastatin [3, 5].
- Antiarrhythmic drug amiodarone [3, 5].
- Calcium channel blocker verapamil [3].
- Antimalarials: amodiaquine and chloroquine [3, 4, 7].
- Antiepileptic carbamazepine [5].
- NSAIDs: diclofenac, ibuprofen [5].
- The anti-asthmatic montelukast [8].
CYP2C8 also metabolizes:
- Retinoic acid [4, 9].
- Arachidonic acid to epoxyeicosatrienoic acids (EETs) [4, 3, 9].
This enzyme processes many of the drugs that are also processed by CYP3A4. Both enzymes are increased by PXR, CAR and the glucocorticoid receptor [9, 3, 2].
CYP2C8 Location
This enzyme accounts for 7% of total CYP enzyme content in the liver [9].
Apart from the liver, it can be found in the brain, adrenal gland, ovary, breast, kidney, lung, gut, tonsils, mucus lining of the nose, arteries, blood vessels, and heart [3, 5].
CYP2C8 The Good
This enzyme can help with blood vessel inflammatory diseases. It helps by increasing the level of epoxyeicosatrienoic acids (EETs) [10].
EETs are beneficial because they decrease blood vessel inflammation. They also decrease oxidative stress by decreasing reactive oxygen species [10].
EETs also induce blood vessel relaxation and promote heart recovery in ischemia-reperfusion injury [5]. Ischemia-reperfusion injury typically happens when there is decreased blood supply to the heart, due to hardening of the arteries or a heart attack.
CYP2C8 The Bad
High levels of this enzyme can be found in breast cancer [5].
CYP2C8 activity may be both protective and damaging to the heart. A study shows that CYP2C8 can increase heart injury. Decreasing this enzyme reduces infarct size in mice [5].
CYP2C8 Gene Polymorphism
RS11572080 and RS10509681
These two SNPs together form what is known as the CYP2C8*3 variant.
The CYP2C8*3 variant is rare in African-Americans but has been reported in as many as 20% of Whites [5].
Carriers of this variant have significantly higher enzyme activity (210 leukemia patients) [11].
People with CYP2C8*3 have increased clearance of CYP2C8-processed drugs, such as repaglinide, rosiglitazone, and pioglitazone [9, 4].
CYP2C8*3 carriers have a reduced therapeutic response to rosiglitazone. But they also have a lower risk of developing edema as a side-effect during treatment (187 patients) [12].
On the other hand, carriers of CYP2C8*3 are more likely to have a better response to paclitaxel treatment. However, they are also at increased risk of experiencing severe nerve damage (peripheral neuropathy) as a side-effect (111 and 209 patients) [13, 14].
People with these variants (rs11572080; rs10509681) show a higher risk of developing acute gut bleeding during the use of NSAIDs metabolized by CYP2C8 [15]. These include diclofenac and ibuprofen.
CYP2C8*3 increases the risk of hypertension (high blood pressure) in men by twofold. This effect is not seen in women. These difference between sexes may partly be explained by the beneficial effect of estrogen (949 subjects) [16].
RS1058930
This SNP is also known as the CYP2C8*4 variant.
Carriers have lower enzyme activity (210 leukemia patients) [11].
CYP2C8*4 have more than 50% higher blood imatinib levels (210 leukemia patients) [11].
RS11572103
This variant is also known as CYP2C8*2.
The CYP2C8*2 variant occurs in less than 1% of Whites and about 15% of African-Americans [5].
CYP2C8*2 variant results in poor drug metabolizers (people with low enzyme activity).
This variant was associated with chloroquine-resistant malaria infections [17].
RS1934951
Multiple myeloma patients on bisphosphonate therapy can sometimes develop a severe complication called bisphosphonate-related osteonecrosis of the jaws (BONJ). rs1934951 A/A and A/G predict multiple myeloma patients at high risk to develop BONJ (meta-analysis, 5 studies, 126 cases, and 453 controls) [18].
RS1058932
rs1058932 T is associated with an increased risk of heart attack in men (5199 subjects) [19].
- RS1113129
- RS11572177
- RS1341164
- RS17110453
- RS1934953
- RS1934954
- RS1934955
- RS2071426
- RS2185570
- RS2860975
- RS4918798
- RS72820627
Increasing or Decreasing CYP2C8
These increase CYP2C8:
- rifampicin, phenobarbital, and CITCO [3].
- phenytoin, hyperforin, paclitaxel, and dexamethasone [3].
- PPARα [4].
- estrogens [16].
These decrease CYP2C8:
- Starfruit juice [20].
- Licochalcone A, a major compound in traditional Chinese herbal licorice [21].
- Quercetin [22].
- Cranberry extract [23].
- Saw palmetto extracts [23].
- Garlic, echinacea, valerian, black cohosh [23].
- Eurycoma longifolia, Labisia pumila, Echinacea purpurea, Andrographis paniculata, and Ginkgo biloba [24].
- WNT/β-catenin [4].
- Cholesterol-lowering gemfibrozil [25, 26]
- Acyl glucuronide metabolites of clopidogrel and deleobuvir [25, 6].
- Losartan [27].
