CYP2C19

• Cytochrome P450 2C19 (abbreviated CYP2C19) is an enzyme protein.
• CYP2C19 is a member of the cytochrome P450 enzyme family, which plays a significant role in the metabolism of various drugs in the body.
• It is a member of the CYP2C subfamily of the cytochrome P450 mixed-function oxidase system.
• This subfamily includes enzymes that catalize metabolism of xenobiotics, including some proton pump inhibitors and antiepileptic drugs.
• In humans, it is the CYP2C19 that encodes the CYP2C19 protein.
• The CYP2C19 enzyme is primarily expressed in the liver and is responsible for the metabolism of a wide range of medications, including certain antidepressants, anticoagulants, proton pump inhibitors, and antiplatelet drugs.
• Genetic variations in the CYP2C19 gene can affect the activity of the enzyme, leading to variability in drug metabolism among individuals.

Protein CYP2C19 PDB 1r9o

Proportion of drugs metabolized by different CYPs

Drug Metabolism by CYP2C19

• CYP2C19 metabolizes drugs through oxidation reactions, which involve adding an oxygen atom to the drug molecule, facilitating its breakdown and elimination from the body.
• The enzyme is responsible for both phase I metabolism, where the drug molecule is modified to a more polar form, and phase II metabolism, where the modified drug molecule is further conjugated with other molecules to enhance its elimination.
• The activity of CYP2C19 can vary significantly among individuals due to genetic polymorphisms.
• These polymorphisms result in different phenotypes, including extensive metabolizers (EMs), intermediate metabolizers (IMs), poor metabolizers (PMs), and ultra-rapid metabolizers (UMs).
• The different phenotypes can lead to variations in drug response and therapeutic outcomes.

Clinical Significance

• The activity of CYP2C19 has significant clinical implications, as it affects the metabolism and efficacy of several medications.

Some examples include:

1. Proton Pump Inhibitors (PPIs):

• CYP2C19 is involved in the metabolism of certain proton pump inhibitors, such as omeprazole, lansoprazole, and pantoprazole.
• Poor metabolizers of CYP2C19 may have reduced drug metabolism, leading to higher drug concentrations and an increased risk of adverse effects.

2. Anticoagulants:

• CYP2C19 plays a role in the metabolism of certain anticoagulant medications, including clopidogrel.
• Poor metabolizers of CYP2C19 may have decreased activation of clopidogrel, resulting in reduced effectiveness in preventing blood clotting.
• Alternative antiplatelet medications may be considered for individuals with reduced CYP2C19 activity.

3. Antidepressants:

• Some antidepressants, such as citalopram and escitalopram, undergo metabolism by CYP2C19.
• Genetic variations in CYP2C19 can affect the clearance of these drugs from the body, leading to variations in drug response and potential differences in efficacy and side effects.

Genetic Polymorphisms

• Genetic polymorphisms in the CYP2C19 gene can result in different enzyme activities and affect drug metabolism.

The most common genetic variants include:

1. *1 Allele (Wild Type):

• The *1 allele is associated with normal enzyme activity and is considered the wild type.

2. *2 Allele:

• The *2 allele is associated with reduced enzyme activity.
• Individuals with two copies of the *2 allele are classified as poor metabolizers (PMs), while those with one copy are intermediate metabolizers (IMs).

3. *3 Allele:

• The *3 allele is another variant associated with reduced enzyme activity.
• Similar to the *2 allele, individuals with two copies of the *3 allele are classified as poor metabolizers.

4. *17 Allele:

• The *17 allele is associated with increased enzyme activity.
• Individuals carrying this allele may be classified as ultra-rapid metabolizers (UMs) and may require adjusted dosages for medications metabolized by CYP2C19.

• Genetic testing for CYP2C19 polymorphisms may be considered in certain clinical scenarios to guide drug selection and dosage adjustments, especially for medications with a narrow therapeutic index.

Drug Interactions

• CYP2C19 can also be affected by drug interactions, where certain medications can either inhibit or induce the enzyme's activity.

Some medications that may interact with CYP2C19 include:

• Inhibitors: Fluoxetine, fluvoxamine, omeprazole, esomeprazole, cimetidine, fluconazole, and ticlopidine are examples of medications that can inhibit CYP2C19 activity, leading to reduced drug metabolism and potential drug interactions.
• Inducers: Rifampin, carbamazepine, phenytoin, and St. John's wort are examples of medications that can induce CYP2C19 activity, potentially increasing the metabolism of drugs metabolized by CYP2C19 and reducing their effectiveness.

• It's important to consider potential drug interactions and adjust medication dosages when necessary, particularly for medications metabolized by CYP2C19, to optimize therapeutic outcomes and minimize the risk of adverse effects.

Other Names

• Besides its official name, CYP2C19, this gene and its corresponding enzyme are known by other names as well:

S-mephenytoin 4'-hydroxylase:

• CYP2C19 gained its initial recognition as the enzyme responsible for the metabolism of the anticonvulsant medication, mephenytoin.
• The ability of CYP2C19 to metabolize S-mephenytoin into its 4'-hydroxylated form led to the identification of this gene and subsequent investigations into its broader substrate specificity.

P450IIC19:

• CYP2C19 was originally classified as a member of the cytochrome P450 superfamily and designated as P450IIC19, indicating its membership in the CYP2 subfamily.

Mephenytoin hydroxylase:

• As CYP2C19's role in the metabolism of mephenytoin was discovered early on, it was also referred to as mephenytoin hydroxylase.

These fallowing alternative names may be encountered in scientific literature or discussions related to CYP2C19.

• R)-limonene 6-monooxygenase
• (S)-limonene 6-monooxygenase
• (S)-limonene 7-monooxygenase
• CPCJ
• CYP2C
• CYPIIC17
• CYPIIC19
• cytochrome P-450 II C
• cytochrome P450 2C19 precursor
• cytochrome P450, subfamily IIC (mephenytoin 4-hydroxylase), polypeptide 19
• cytochrome P450-11A
• cytochrome P450-254C
• flavoprotein-linked monooxygenase
• mephenytoin 4'-hydroxylase
• mephenytoin 4-hydroxylase
• microsomal monooxygenase
• P450C2C
• xenobiotic monooxygenase

See Also

• Cytochrome P450 Enzymes
• Pharmacokinetics
• Genetic Polymorphism
• Drug Metabolism

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