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Cytochrome p450 2c19 (cyp2c19) 10 mutations

Cytochrome P450 2C19
(CYP2C19) 9 Mutations
FOR DETECTION OF CYP2C19 MUTATIONS AFFECTING DRUG concentrations of the parent drug and slower clearance. Carriers Clinical Background
of CYP2C19*17 may exhibit lower plasma concentrations • Cytochrome P450 2C19 (CYP2C19) is an isoenzyme of the and higher clearance. Therapeutic drug monitoring should be cytochrome P450 super family that metabolizes and eliminates common prescription drugs, including anti-convulsants, anti- ◦ Tamoxifen (Nolvadex®): Carriers of CYP2C19 *17 have depressants, proton pump inhibitors, and antithrombotics been shown to produce higher concentrations of the active (clopidogrel/Plavix®), as well as chemotherapy, anti-malaria, and metabolite endoxifen and experience decreased breast cancer recurrence when treated with tamoxifen. Decrease function alleles (e.g., CYP2C19 *9) are not expected to affect response • Pharmacogenetic variation leads to inappropriate concentrations of drugs and drug metabolites, which may contribute to toxicity and risk of adverse drug reactions or lack of therapeutic benefit. • For individuals with a personal or a family history of adverse drug reactions to medications metabolized by CYP2C19.
• Metabolizer phenotypes can be predicted by the CYP2C19 Interpretation
• The clinical impact of the CYP2C19 genotype is influenced by whether a drug is activated (e.g., clopidogrel, tamoxifen) or • If no CYP2C19 mutations are detected, this suggests *1 alleles inactivated (e.g., amitryptiline, escitalopram) by CYP2C19, involvement of other metabolic pathways, and other non-genetic • If one decreased function or one non-functional CYP2C19 factors (e.g., concomitant medications).
mutation is detected, intermediate-to-normal CYP2C19 Epidemiology
• If two decreased function alleles, or one decreased function and • CYP2C19 mutation frequency is dependent on ethnicity. The one non-functional allele are detected, intermediate CYP2C19 most common mutations are represented by the *2 and *3 alleles. • The *2 allele is found in approximately 30% of Asians and 15% • If two non-functional mutations are present on opposite alleles, this predicts low CYP2C19 enzymatic activity and a poor • The *3 allele is present in approximately 8% of Asians and is rare (less than 1%) in Caucasians and African-Americans.
• Heterozygosity or homozygosity for the increased function *17 allele is associated with increased CYP2C19 activity and an • A poor metabolizer phenotype (caused by two non-functional CYP2C19 alleles) is present in 4% of Caucasians, 5% of African- • Genotype results should be interpreted in the context of the individual clinical situation. Consultation with a clinical Genetics
pharmacy professional is recommended.
• The CYP2C19 gene has nine exons and is located on chromosome Methodology
• Polymerase chain reaction (PCR) followed by detection primer • Inheritance is autosomal recessive. Indications for Ordering
Nucleotide
Mutation
Predicted
Designation Change
• Pre-therapeutic testing to identify individuals who should avoid, Activity
or may require unconventional doses of medications metabolized ◦ Clopidogrel (Plavix®): Carriers of CYP2C19 *2 or *3 alleles have been shown to respond poorly to standard doses due to reduced metabolic activation of the drug. An alternate drug or dose escalation, coupled with monitoring of platelet function, ◦ Amitriptyline (Elavil®) and escitalopram (Lexapro®): Carriers of CYP2C19 *2 or *3 alleles may exhibit higher plasma 2012 ARUP LABORATORIES. ALL RIGHTS RESERVED. JANUARY 2012
500 Chipeta Way, Salt Lake City, UT 84108 | (800) 522-2787 | (801) 583-2787 | | ARUP is an enterprise of the University of Utah and its Department of Pathology. Nucleotide
Mutation
Predicted
• Drug metabolism may be affected by non-genetic factors.
Designation Change
• Mutation detection is not a substitute for therapeutic drug or Activity
• Rare diagnostic errors may occur due to primer-site mutations.
Related Tests
• Cytochrome P450 2C9 (CYP2C9) 2 Mutations () • Cytochrome P450 2D6 (CYP2D6) 14 Mutations & Gene References
1. Goldstein JA and de Morais SM. Biochemistry and molecular biology of the human CYP2C subfamily. Pharmacogenetics 2. Streetman DS, Bertino JS, Jr., and Nafziger AN. Phenotyping of drug-metabolizing enzymes in adults: a review of in-vivo cytochrome P450 phenotyping probes. Pharmacogenetics 3. Flockhart DA. Drug Interactions: Cytochrome P450 Drug • Clinical sensitivity is estimated at 99% and 87% for Asians Interaction Table. Indiana University School of Medicine (2007). and Caucasians, respectively; sensitivity is unknown in other http://medicine.iupui.edu/clinpharm/ddis/table.asp. (accessed on • Analytical sensitivity and specificity are 99%.
4. Mega JL, et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med 2009;360(4):354–362. Limitations
5. Simon T, et al. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med 2009;360(4):363–375. • CYP2C19 mutations, other than those listed above, are not • Mutations in other genes associated with drug metabolism or Test Information
For specific collection, transport, and testing information, refer to the ARUP website at .
For information on test selection, ordering, and interpretation, refer to ARUP Consult® at ARUP LABORATORIES | JANUARY 2012

Source: http://arupcs.com/Testing-Information/resources/TechnicalBulletins/January%202012/Cytochrome%20P450%202C19%20(CYP2C19)%209%20%20Mutations.pdf

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