Cytochrome P450 3A4 Genotype, Saliva
Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
The cytochrome P450 (CYP) 3A4 enzyme is responsible for the metabolism of approximately 50% of drugs that undergo hepatic metabolism and first pass metabolism in intestinal epithelial cells, including lipid-lowering drugs. The CYP3A4 enzyme activity is highly variable.(1) While polymorphisms and mutations have been described for the CYP3A4 gene, they do not explain the highly variable enzymatic activity of the encoded protein.(2) A CYP3A4 (c522-191C->T) intron 6 polymorphism (CYP3A4*22) affects hepatic expression of CYP3A4 and response to statin drugs. The CYP3A4*22 allele is associated with reduced CYP3A4 activity, resulting in a better response to lipid-lowering drugs, such as simvastatin, atorvastatin, or lovastatin. Studies show that CYP3A4 mRNA level and enzyme activity in the liver with CC genotype were 1.7- and 2.5-fold greater than in CT and TT carriers, respectively. In 235 patients taking stable doses of drugs for lipid control, carriers of the T allele required significantly lower statin doses for optimal lipid control than did non-T carriers.(3) These results indicate that CYP3A4*22 markedly affects expression of CYP3A4 and could serve as a biomarker for CYP3A4 metabolizer phenotype. The reported allele frequency of CYP3A4*22 in Caucasians was 5% to 8%. The allele frequency is 4.3% in African Americans and in Chinese.
See Cytochrome P450 3A4 and 3A5 Known Drug Interaction Chart in Special Instructions.
An aid to clinicians in determining therapeutic strategies for drugs that are metabolized by CYP3A4, including atorvastatin, simvastatin and lovastatin
Genotyping patients who prefer not to have venipuncture done
The CYP3A4*22 (c.522-191C->T) allele was not identified (ie, CC genotype detected) in this individual. This genotype predicts higher CYP3A4 enzyme activity. Individuals with this genotype may require higher statin doses for optimal therapy.
This individual is heterozygous (CT) for the CYP3A4*22 (c.522-191C->T) allele. This genotype predicts lower CYP3A4 enzyme activity. Individuals with this genotype may require lower statin doses.
This individual is homozygous (TT) for the CYP3A4*22 (c.522-191C->T) allele. This genotype predicts lower enzyme activity. Individuals with this genotype may require significantly lower statin doses.
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
Note that in patients who have received heterologous blood transfusions before a saliva sample was acquired, the saliva samples may contain donor DNA. Return to recipient genotype usually occurs after 6 weeks. Similarly, saliva samples obtained from patients after allogeneic blood or marrow transplantation can contain donor DNA. In both cases, this may result in genotyping results that reflect the genotype of the recipient, the donor, or a blend of the donor and recipient. Results obtained under these circumstances may not accurately reflect the recipient’s genotype.
CYP3A4 genetic test results in patients who have undergone liver transplantation may not accurately reflect the patient's CYP3A4 status.
This test does not detect polymorphism or mutations other than the specific intron 6 polymorphism.
This test is not indicated for stand-alone diagnostic purposes.
This test is not intended to be used to predict drug response.
Drug-drug interactions and drug/metabolite inhibition must be considered.
Drug/metabolite inhibition can occur, resulting in inhibition of CYP3A4 catalytic activity.
Patients may also develop toxicity problems if liver and kidney function are impaired.
CYP3A4 genotyping should not be ordered for managing patients receiving fluvastatin, rosuvastatin, or pravastatin since these drugs are NOT metabolized appreciably by CYP3A4.
Rare polymorphisms exist that could lead to false-negative or false-positive results. If results obtained do not match the clinical findings, additional testing could be considered.
Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.
An interpretive report will be provided.
Clinical References Provides recommendations for further in-depth reading of a clinical nature
1. Evans WE, Relling RV: Pharmacogenomics: translating functional genomics into rational therapeutics. Science 1999;486:487-491
2. Lamda JK, Lin YS, Schuetz EG, Thummel KE: Genetic contribution to variable human CYP3A-mediated metabolism. Adv Drug Deliv Rev 2002;18:1271-1294
3. Wang D, Guo Y, Wrighton SA, et al: Intronic polymorphism in CYP3A4 affects hepatic expression and response to statin drugs. Pharmacogenomics J 2011;11:274-286
4. Elens L, Becker ML, Haufroid V, et al: Novel CYP3A4 intron 6 single nucleotide polymorphism is associated with simvastatin-mediated cholesterol reduction in the Rotterdam study. Pharmacogenet Genomics 2011;21(12):861-866
5. Elens L, Van Schaik RH, Panin N, et al: Effect of a new functional CYP3A4 polymorphism on calcineurin inhibitor’ dose requirements and trough blood levels in stable renal transplant patients. Pharmacogenomics 2011;12(10):1383-1396