CYP2C9 Gene – An Introduction
The CYP2C9 gene is located on chromosome 10 and contains instructions for the production of the enzyme with the same name. The CYP2C9 enzyme participates in phase I detoxification.
It is primarily present in the liver and is involved in the metabolism of many drugs, xenobiotics (foreign substances present in the body that are not produced by it), and endogenous compounds like steroid hormones and fatty acids.
Metabolism is the process by which large and complex things like food molecules and medicines are broken down into smaller components to produce energy, build or repair body tissue, produce hormones, etc.
The CYP2C9 enzyme also plays a significant role in the metabolism of warfarin, a blood-thinning drug (anticoagulant) used to prevent clotting inside the blood vessels.
Reduced warfarin metabolism results in slower clearance of the drug. As a result, it stays longer in the body and can lead to poor blood clotting and the risk of excessive bleeding. People who are slow metabolizers of warfarin may benefit from a lower starting dose.
CYP2C9 – The Different Metabolizer Types
Normal Metabolizers: Individuals with *1/*1 alleles of the CYP2C9 gene are said to be normal metabolizers of warfarin. They have normal circulating levels of the CYP2C9 enzyme.
Intermediate Metabolizers: Individuals who have one normal allele and one decreased function allele are said to be intermediate metabolizers of the gene. They tend to have either CYP2C9 *1/*2 or *1/*3 alleles.
Poor Metabolizers: People having CYP2C9 *2/*2 type and *3/*3 type ( homozygous for these alleles) are slow or poor metabolizers of warfarin and therefore require lower doses of the drug in order to prevent excessive bleeding.
Drugs That The CYP2C9 Gene Acts On
While the CYP2C9 gene is mostly studied for warfarin metabolism, the gene is responsible for the metabolism and clearance of other drugs such as:
- Ibuprofen: Is an anti-inflammatory drug
- Losartan: A commonly used anti-hypertensive drug
- Tolbutamide: A drug used to manage type 2 diabetes
- Glipizide: An oral anti-diabetic medication used to treat type 2 diabetes.
- Celecoxib: A drug used as a pain reliever in conditions like arthritis, spondylitis, painful menstruation, and rheumatoid arthritis.
- Montelukast: A medication used in the treatment of asthma and allergic rhinitis.
- Naproxen: An NSAID drug used for pain and inflammation relief.
Abnormal changes in the CYP2C9 gene can affect enzyme production, i.e., they can increase or decrease its activity. This is important because the activity of the CYP2C9 gene affects how your body will respond to different doses of commonly used drugs.
CYP2C9 Inducers and Inhibitors
Drugs that Induce CYP2C9 Activity
- Rifampicin: An antibiotic that is used as a front-line drug in the treatment of tuberculosis.
- Carbamazepine: Is an anticonvulsant that is used to treat epilepsy and neuropathic pain.
- Ethanol: A psychoactive drug that is the primary ingredient in hard liquor.
- Phenobarbitone: A barbiturate drug that is used in the treatment of epilepsy.
Drugs that Inhibit CYP2C9 Activity
Inhibitors lower the levels of CYP2C9 enzyme activity. As a result, the drugs this enzyme acts on are not cleared efficiently from the body. Some CYP2C9 inhibitors include:
- Clopidogrel: A commonly used anticoagulant used to prevent heart conditions and stroke. Clopidogrel is often used along with aspirin in heart attack cases and in patients with a coronary artery stent.
- Disulfiram: A drug used to treat chronic alcoholism.
- Fluconazole: An antifungal medication used in the treatment of candidiasis, pityriasis Versicolor, and other fungal diseases.
- Metronidazole: A commonly used antibiotic and antiprotozoal drug. This drug acts on anaerobic bacteria and effectively treats conditions like pelvic inflammatory disease, endocarditis, and bacterial vaginosis.
- Valproic Acid: A drug used in the treatment of epilepsy and bipolar disorder. It is also used for migraine headaches.
Variations in the CYP2C9 gene
There are over 50 variants (or types) of the CYP2C9 gene that affect enzyme activity. Many variants of this gene are important as they increase or decrease enzyme activity.
| Haplotype | Effect |
| CYP2C9*2 | Decreased enzyme activity |
| CYP2C9*3 | Decreased enzyme activity |
| CYP2C9*5 | Decreased enzyme activity |
| CYP2C9*6 | Decreased enzyme activity |
| CYP2C9*8 | Decreased enzyme activity |
| CYP2C9*11 | Decreased enzyme activity |
| CYP2C9*13 | Decreased enzyme activity |
A haplotype is a group of gene changes that are inherited together. The *3, *4, *14, *41, etc., are star alleles. Star alleles are used to name different haplotypes.
The two most commonly studied variants of this gene are the CYP2C9*2 and CYP2C9*3.
CYP2C9*2 and Warfarin Sensitivity
In CYP2C9*2, the amino acid arginine is replaced by cysteine at a specific part of the gene. This reduces CYP2C9 enzyme activity, and this leads to a decrease in warfarin metabolism. So people who have CYP2C9*2 are at an increased risk for warfarin sensitivity.
Having two copies of the T allele reduces warfarin processing and clearance by 40% whereas, having one normal C and one risk allele T reduces warfarin processing and clearance by 20%.
Individuals with two T alleles also showed a lower clearance of drugs like phenytoin, tolbutamide, ibuprofen, fluvastatin, and phenprocoumon.
CYP2C9*3
The second common type of the CYP2C9 variant is the CYP2C9*3. Here, the *3 allele denotes the risk allele C.
One copy of the C allele reduces warfarin metabolism by 40%. Having two copies of the C allele reduces it by 80%. This variant is also associated with a decrease in THC(cannabis) metabolism.
The CC type is also associated with decreased clearance of other drugs like tolbutamide, fluvastatin, glimepiride, tenoxicam, candesartan, celecoxib, and phenytoin.
People having the AC type show a decreased clearance and a longer half-life of the drug flurbiprofen.
Recommendations for Optimum CYP2C9 Gene Function
Genetic Testing
Individuals who require anticoagulants are advised to undergo genetic testing to detect any abnormal changes in the CYP2C9 gene. This helps the healthcare provider prescribe the appropriate dose of drugs like warfarin.
Genetic variants of the CYP2C9 gene are important because they metabolize different types of drugs in different ways:
- Altered functioning of the CYP2C9 gene can increase the risk of stomach bleeding with NSAIDs.
- Individuals having reduced enzyme activity should be started on a lower dosage of the drug celecoxib (an anti-inflammatory drug).
- It has been recently found that individuals who have the slow metabolizing variant of the CYP2C9 gene had a greater reduction of LDL (bad cholesterol levels) when prescribed rosuvastatin.
Avoid Hesperidin-rich Food
Foods like oranges, lemons, and others are rich in hesperidin, a flavonoid that inhibits the CYP2C9 gene and its activity. This is more important for individuals who are on anticoagulant therapy with warfarin.
Avoid Short-Term Fasting
People taking any drug that is metabolized by the CYP2C9 gene must avoid taking the medication right after a short-term fast. A 36-hour fast is said to reduce CYP2C9 activity by 19%, and this can affect blood clotting time if the individual is taking warfarin.
Switch to Non-aspirin Alternative
Individuals taking aspirin to reduce their risk of colon cancer and have reduced activity of the CYP2C9 enzyme must switch to a non-aspirin alternative to avoid complications.
Summary
- The CYP2C9 gene, located on chromosome 10, gives instructions for the production of the CYP2C9 enzyme, which participates in phase I of the detoxification process.
- This enzyme is primarily produced in the liver and is involved in the metabolism of endogenous toxins, xenobiotics, drugs, steroid hormones, and fatty acids.
- CYP2C9 activity primarily influences warfarin metabolism. Any abnormal variation in the CYP2C9 gene can increase or decrease the enzyme activity.
- CYP2C9*2 and *3 types are associated with lower production of the enzyme.
- People with these variants are at an increased risk for warfarin sensitivity and may benefit from a lower starting dose.
- Genetic testing is highly recommended for people who need anticoagulant therapy or drugs that are metabolized by the CYP2C9 gene.
- Individuals with impaired CYP2C9 activity may need to avoid hesperidin-rich fruits and observing a short-term fast, as both of these reduce warfarin metabolism.
References:
- https://medlineplus.gov/genetics/gene/cyp2c9/#resources
- https://www.genecards.org/cgi-bin/carddisp.pl?gene=CYP2C9
- https://www.pharmgkb.org/vip/PA166169913
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6708768/
- https://www.pharmgkb.org/vip/PA166169913
- https://pubmed.ncbi.nlm.nih.gov/12698304/
- https://pubmed.ncbi.nlm.nih.gov/26554252/
- https://pubmed.ncbi.nlm.nih.gov/28229374/
