CYP2C19 Gene – An Introduction
The CYP2C19 gene is a member of the cytochrome P450 family responsible for the detoxification of drugs and toxins from the body.Â
The CYP2C19 gene is primarily found in the liver and provides instructions for the production of the enzyme that participates in the metabolism of at least 10% of commonly prescribed medications.Â
An important substrate that the CYP2C19 acts upon is Clopidogrel, an antiplatelet drug. Abnormal changes in the CYP2C19 gene contribute to clopidogrel resistance by affecting enzyme activity. In such individuals, the drug is less effective than in people with the normally functioning enzyme.
CYP2C19 Gene – The Different Metabolizer Types
Considerable differences exist in the efficiency and amount of CYP2C19 enzyme produced across individuals. Depending on this, they are categorized into one of the four metabolizer statuses:
Ultrarapid metabolizers
As the name goes, these individuals have higher than normal levels of the CYP2C19 enzyme. It occurs when a person has one or two copies of a form (variant) of the CYP2C19 gene called CYP2C19*17.
<5% of Asians carry this variant.
These individuals are resistant to proton pump inhibitors (PPI) therapy. PPIs are used to treat Gastroesophageal Reflux Disease (GERD), gastric or duodenal ulcer, H.Pylori infection, and NSAID damage.
Extensive metabolizers or Normal metabolizers
Individuals having at least one copy of CYP2C19*1 are considered to be extensive or normal metabolizers. They have normal levels of the CYP2C19 enzyme.
Poor metabolizers
The variants CYP2C19*2 and CYP2C*3 results in loss of function of the gene and cause low enzyme activity. They are called null variants. Individuals having these variants are called poor metabolizers.
Around 10% of people are poor metabolizers, and the antiplatelet drug Clopidogrel has little or no effect on these people. So, alternate antiplatelet drugs are prescribed to them.
Blood levels of the drug amitriptyline ( a cyclic antidepressant) are found to be high in poor metabolizers. A lower starting dose may benefit these individuals.
Similarly, the blood levels of voriconazole (an antifungal drug) are found to be high in these individuals, and treatment using this drug usually begins with lower doses.
Compounds That The CYP2C19 Gene Acts On
The CYP2C19 gene acts upon many prescribed drugs and medications. Common substrates of this gene include:
- Antidepressants
- Benzodiazepines
- Mephenytoin
- Proton Pump Inhibitors
- Anticonvulsants
- Methadone
- MDMA or ecstasy
While some substrates induce (or increase) the activity of the gene, some substances reduce it.
Studies have shown a reduced activity of the CYP2C19 gene in women who take oral contraceptives. This is said to occur because the metabolic product of the oral contraceptive reduces the CYP2C19 function.
The CYP2C19 enzyme helps to convert arachidonic acid (a healthy omega-6 fatty acid that is beneficial for health, especially in infants) into Epoxyeicosatrienoic acids (EETs). These EETs have a beneficial and protective effect on the heart and blood vessels.
A study reported that reduced activity of the CYP2C19 enzyme is associated with heart disease.
Higher activity of the CYP2C19 gene has been associated with depression. Also, low CYP2C19 activity has been associated with a lower prevalence of major depressive disorder and depression symptoms.
CYP2C19 Inducers and Inhibitors
Inducers are substances that increase the activity of an enzyme whereas inhibitors are substances that bind to an enzyme to reduce its activity.
Drugs that Induce CYP2C19 Activity
- Carbamazepine: An anticonvulsant medication that is used in the treatment of epilepsy and neuropathic pain.
- Barbiturates: Is used an anxiolytic, hypnotic and anticonvulsant medication.
- Phenytoin: Used in the treatment of epilepsy
- Rifampin: An antibiotic used in the treatment of tuberculosis
- Primidone: An anti-epileptic medication used in treating partial and generalized seizures.
Drugs that Inhibit CYP2C19 Activity
- Chloramphenicol
- Clopidogrel: An antiplatelet medication that is used to reduce the risk of heart disease and stroke.
- Fluconazole: Used in the treatment of fungal infections
- Omeprazole: Used to treat acidity, Gastroesophageal Reflux Disease (GERD), Zollinger-Ellison Syndrome, and peptic ulcers.
- Cimetidine: Used to control the amount of acid produced in the stomach in the treatment of acidity, heartburn, and peptic ulcers.
Variations in the CYP2C19 Gene
There are over 30 known variants (or types) of the CYP2C19 gene.
| Haplotype | Effect |
| CYP2C19*2 | Inactive (Non functional variant) |
| CYP2C19*3 | Inactive (Non functional variant) |
| CYP2C19*4 | Inactive (Non functional variant) |
| CYP2C19*5 | Inactive (Non functional variant) |
| CYP2C19*6 | Inactive (Non functional variant) |
| CYP2C19*7 | Inactive (Non functional variant) |
| CYP2C19*8 | Decreased enzyme activity |
| CYP2C19*17 | Decreased enzyme activity |
| CYP2C19*27 | Decreased enzyme activity |
A haplotype is a group of gene changes that are inherited together. The *3, *4, *17, *27, etc., are star alleles. Star alleles are used to name different haplotypes.
The commonly studied variants are CYP2C19 *2, *3, and *17.
CYP2C19*2
This is the most common type seen in the Caucasian population. This type reduces the activity of the CYP2C19 gene, reduces the metabolism of certain drugs, and increases the risk of cardiovascular diseases.
CYP2C19*3
The presence of this type of gene reduces the metabolism of commonly prescribed drugs in individuals.
CYP2C19*17
Individuals who are carriers of this variant of the CYP2C19 gene show aggravated response to Clopidogrel and have an increased risk of bleeding.
Recommendations For Optimum CYP2C19 Activity
- Avoid making significant changes to their lifestyle and diet
Individuals with excessive or reduced activity of the CYP2C19 gene are advised against making significant changes to their diet, lifestyle, or taking supplements with their healthcare provider.
- Genetic Testing
Genetic testing is recommended for individuals who need to be prescribed medications that the CYP2C19 gene acts on to determine the right alternative and the appropriate dosage.
For Poor Metabolizers
- Clopidogrel must not be prescribed in these individuals
- Voriconazole and amitriptyline must be given only in reduced doses
For Ultra Rapid Metabolizers
- If lansoprazole, omeprazole, or pantoprazole need to be given in an ultra metabolizer, double the dose may be required to bring about the desired effect.
- Either higher doses of Voriconazole or other anti-fungal alternatives may be required for these individuals.
- Amitriptyline does not provide the desired effect, and an alternative is recommended.
Summary
- CYP2C19 gene is a part of the cytochrome P450 enzymes and participates in the phase I detoxification of drugs (at least 10% of the commonly prescribed drugs).
- The gene has been extensively studied in relation to Clopidogrel, an antiplatelet drug.
- Some common substrates of the CYP2C19 gene include antidepressants, benzodiazepines, mephenytoin, anticonvulsants, among others.
- Some substances increase the activity of the gene (called inducers), and others inhibit (or reduce) its activity.
- The commonly studied variants of the CYP2C19 gene include *2, *3, and *17.
- Based on the presence of these haplotypes, individuals can be grouped under ultra-rapid metabolizers, extensive metabolizers, and poor metabolizers.
- Depending on the type of CYP2C19 gene, dosage changes may be required for drugs like lansoprazole, amitriptyline, and voriconazole can be prescribed.
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