What is CYP2C9?
CYP2C9 is one of the cytochrome P450 monooxygenases (CYPs). These are enzymes that eliminate most of the drugs and toxins from the human body .
CYP2C9 is responsible for the metabolic clearance of up to 15-20% of all drugs undergoing Phase I detoxification .
This enzyme is the third most important cytochrome P450 (CYP) in terms of the number of drugs metabolized .
This enzyme metabolizes:
- Antidiabetics: tolbutamide , nateglinide  and glipizide .
- Antiepileptics: phenytoin  and valproate . CYP2C9 is responsible for about 90% of phenytoin metabolism .
- Antihypertensive losartan [6, 7].
- Cannabinol .
- Non-steroidal anti-inflammatory drugs (NSAIDs): flurbiprofen , ibuprofen [2, 10], and celecoxib .
- Anticoagulants: warfarin, acenocoumarol, phenprocoumon [3, 12].
- Anti-asthmatic zafirlukast .
- Cholesterol-lowering fluvastatin .
CYP2C9 also metabolizes:
- Lots of internal hormones and compounds, such as progesterone, testosterone and arachidonic acid .
CYP2C9 accounts for ~20% of the total liver CYP content .
CYP2C9 The Good
In the human heart, CYP2C9 produces epoxyeicosatrienoic acids (EETs) from arachidonic acid .
EETs have a protective effect on blood vessels, including vasodilatation (widening of the blood vessels), anti-inflammatory, and antithrombotic effects. They also protect the heart by increasing post-ischemic (low oxygen) function and reducing heart infarct size .
People with higher CYP2C9 activity have a lower risk of colorectal adenoma (colon cancer) (928 subjects) . This suggests that the activity of this enzyme is protective against cancer.
CYP2C9 The Bad
This enzyme can activate some cancer-causing agents found in cigarette smoke.
Unlike the general population, smokers with lower enzyme activity have a lower risk of colorectal adenoma (colon cancer) (928 subjects) .
CYP2C9 Gene Polymorphism
More than 67 variants of CYP2C9 have been identified . Many of these decrease enzyme activity.
Patients with low enzyme activity are at greater risk of developing adverse reactions, especially for CYP2C9-processed drugs with a narrow therapeutic window, such as S-warfarin, phenytoin, glipizide, and tolbutamide [2, 16].
The T variant at this position reduces CYP2C9 activity by approximately 50% . It is also known as the CYP2C9*2 variant.
Patients with the CYP2C9*2 variant require lower doses of warfarin to achieve a similar anticoagulant effect as other patients , and also lower doses of other medication metabolized by this enzyme.
Individuals with this variant are at risk of prolonged bleeding and more frequent severe bleeding with warfarin therapy. They have a higher possibility of low blood sugar levels during glipizide and tolbutamide therapy. Finally, they have more frequent symptoms of overdose in phenytoin therapy [2, 14].
People with this variant also show an increased risk of developing acute gut bleeding during the use of NSAIDs .
People with this variant have reduced bone mineral density, that could contribute to developing osteoporosis (pilot study, 92 subjects) .
This variant increases the risks of colorectal adenoma (colon cancer) (928 subjects) .
Individuals with these variants are at risk of prolonged bleeding and more frequent severe bleeding on warfarin therapy. They have a higher possibility of low blood sugar levels during glipizide and tolbutamide therapy. They also have more frequent symptoms of overdose in phenytoin therapy [2, 21].
This variant may be associated with vitiligo susceptibility (181 subjects) .
People with this variant have reduced bone mineral density, that could contribute to developing osteoporosis (in a pilot study of 92 subjects) .
Men carrying the C variant had an increased risk of heart attack (myocardial infarction). However, women had a decreased risk of heart disease (2827 subjects) .
Finally, C carriers have an increased overall risk of colorectal adenoma (colon cancer) (928 subjects) .
Increasing or Decreasing CYP2C9
These increase CYP2C9:
- Rifampicin. Clearance of CYP2C9-processed drugs is approximately doubled with rifampicin .
- Bisphenol A (BPA) 
- Age 
These decrease CYP2C9:
- Apigenin 
- Starfruit juice 
- Licochalcone A, a major compound in traditional Chinese herbal licorice 
- Caffeic acid, commonly found in plants 
- Quercetin, commonly found in plants 
- African lettuce (L. taraxacifolia) 
- Goldenseal 
- Berberine [32, 33]
- THC, cannabidiol (CBD), and cannabinol (CBN) found in marijuana 
- Amiodarone, fluconazole, and sulphaphenazole