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Cytochrome P-450 1A2 Genotyping
The cytochrome P450 enzyme CYP1A2 acts on 5-10% of drugs in current clinical use. CYP1A2 plays a major role in the metabolism of many commonly used drugs, including clozapine, imipramine, caffeine, fluvoxamine, paracetamol, phenacetin, theophylline, tacrine and others. Furthermore, CYP1A2 activates several aromatic amines and thus is a key enzyme in chemical carcinogenesis. Several studies on the CYP1A2-dependent metabolism of caffeine or phenacetin have demonstrated that this enzyme is expressed in human livers at various levels amongst individuals, suggesting polymorphic control of enzyme activity.
Genelex CYP1A2 DNA test identifies the two major nucleotide variants by PCR-RFLP, providing increased sensitivity and quality performance. Analytical specificity and sensitivity for detection of these mutations are >99%.
Specimen Types
Please call Client Services at 800-523-6487 to obtain specimen kits.
CPT Codes
CYP1A2 Mutation DNA Analysis (provided for your guidance only)
83891, 83892 x2, 83998 x2, 83894 x2, 83912
Clinical Significance
Hyperinduction phenotype: 39 - 47% (Japanese, Egyptian, Caucasian)
Drugs metabolized by this enzyme approximately 5-10%
Low affinity/high capacity enzyme
Cytochrome P450 1A2 (CYP21A2) is a highly polymorphic liver enzyme of the cytochrome P450 super family involved with the metabolism and elimination of 5-10% of commonly prescribed drugs. CYP1A2 is also involved in the metabolic activation of carcinogens from chemical toxins such as those found in cigarette smoke. There is considerable variation in 1A2 metabolic activity due to genetic factors, environmental factors, and drug-drug interactions. CYP1A2 is both inducible and can be inhibited, "turned on or off" by many medications and food-drug interactions. Fluoroquinolones, for example, are metabolized by and inhibit the enzyme CYP1A2. This can prevent the metabolism of concomitant medications such as theophylline and caffeine, causing excess central nervous system side effects and cardiac stimulation. Conversely, smoking may induce CYP1A2, resulting in enhanced metabolism of 1A2 substrates and the potential of sub-therapeutic response. Variation in the levels of CYP1A2 activity could result in increased or decreased capacity to activate substrates.
Genetic polymorphisms in CYP21A2 are common and can affect therapeutic response to drugs. The enzyme activity is expressed at highly variable levels. Three phenotypes are identified: normal induction, diminished induction and hyperinduction.
Genetic polymorphisms in the CYP1A2 gene influence the magnitude of CYP1A2 induction. Two important polymorphisms that cause functional changes in enzymatic activity have been identified in the CYP1A2*1 the wild-type allele. The CYP1A2*1C allele is the result of a single point mutation (-3860 G>A) and is associated with decreased CYP1A2 metabolic activity in comparison to the normal wild-type CYP1A2*1A allele. The CYP1A2*1F allele is the result of a single point mutation (-163 C>A) and is associated with increased induction particularly in smokers in comparison to the wild-type CYP1A2*1A allele. The distribution of CYP1A2 genotypes is as follows: *1F/*1F (nucleotide sequence A/A) ~ 46 %; *1A/*1F (nucleotide sequence C/A) ~ 44%; and *1A/*1A (nucleotide sequence C/C) ~ 10%, indicating that high induction is the most common phenotype.
Detecting genetic variations in drug-metabolizing enzymes is useful for identifying individuals who may experience adverse drug reactions with conventional doses of certain medications. Individuals who possess CYP1A2*1F and/or CYP1A2*1C variants may exhibit different pharmacokinetics (drug levels) than normal individuals. As a result, such individuals may require non-conventional doses of medications that require CYP1A2 for biotranformation. Conversely, medications that do not require CYP1A2 biotranformation may be preferentially selected for patients with potentially impaired CYP1A2 metabolic capacity to avoid adverse drug reactions.
Laboratory Test Interpretation and Dosage Recommendations
Genelex offers improved detection rates using an extended Cytochrome P-450 1A2 DNA variant panel. This test identifies the major nucleotide variants by PCR-RFLP , providing increased sensitivity and quality performance.
| Cytochrome P-450 1A2 Mutations Detected |
| CYP1A2 allele |
Nucleotide change |
Effect on Enzyme Metabolism |
| *1A |
None (wildtype) |
Normal |
| *1C |
-3860G>A |
Decreased |
| *1F |
-163C>A |
Increased Induction |
For additional information see the CYP1A2 allele nomenclature database at
http://www.imm.ki.se/CYPalleles/cyp1a2.htm
Testing places individuals in one of three categories:
- Normal Induction represents the norm for induction of metabolic activity in the presence of an inducer. Genotypes consistent with the normal induction phenotype include two CYP1A2 *1A alleles.
- Diminished Induction represents a lower than normal level of induction in the presence of an inducer. Genotypes consistent with the diminished induction phenotype are those with either one or two CYP1A2*1C alleles.
- Hyperinduction represents a higher than normal level of induction in the presence of an inducer. Induction may be approximately 40% higher in these patients than in those with the normal induction phenotype. Genotypes consistent with the hyperinduction phenotype include one or two CYP1A2*1F alleles. Patients with this phenotype may require an increased dosage of CYP1A2 substrates due to higher than normal rates of drug metabolism in the presence of an inducer.
Doses of CYP1A2 substrates with a narrow therapeutic range should be decreased immediately on cessation of heavy smoking. A stepwise daily dose reduction of approximately 10% until the fourth day after smoking cessation accompanied by therapeutic drug monitoring has been proposed by Faber et al.
Direct DNA testing will not detect all the known mutations that result in decreased or inactive CYP1A2. Absence of a detectable gene mutation or polymorphism does not rule out the possibility that a patient has an intermediate or poor metabolizer phenotype. This test does not detect polymorphisms other than those listed. Other polymorphisms in the primer binding regions can affect the testing, and ultimately, the genotyping assessments made. Therapeutic drug monitoring is recommended in patients with metabolic variations.
Drug Metabolism Guide
This list is not all inclusive and is for your guidance only.
Substrates Metabolized through Cytochrome P-450 1A2
Substrates refers to drugs that are either activated or deactivated by the pathway.
| Acetominophen |
Gregafloxacin |
Ropinirole |
| amitriptyline |
haloperidol |
Ropivacaine |
| caffeine |
Imipramine |
R-warfarin |
| chlordiazepoxide |
Melatonin |
Tacrine |
| Chloropromazine |
Mesoridazine |
tamoxifen |
| Clomipramine |
Mexiletine |
theophylline |
| Clozapine |
Mibefradil |
Thioridazine |
| cyclobenzaprine |
Mirtazapine |
Thiothixene |
| Dacarbazine |
naproxen |
Toremifrene |
| diazepam |
olanzapine |
Trifluoperazine |
| duloxetine |
Ondansetron |
Verapamil |
| estrogens |
Perphenazine |
Ziprasidone |
| Fluphenazine |
Phenacetin |
Zolmitriptan |
| Flutamide |
Propafenone |
Zolpidem |
| Fluvoxamine |
Propanolol |
|
| Frovatriptan |
Riluzole |
|
Inhibitors of Cytochrome P-450 1A2
Inhibitors refers to drugs that reduce the ability of the pathway to process drugs.
Co-administration will decrease the rate of metabolism of drugs through the metabolic pathway listed, increasing the possibility of toxicity.
| Anastrozole |
isoniazid |
Phenacetin |
| caffeine |
Lidocaine |
Propafenone |
| Cimetidine |
Lomeflozacin |
Ranitidine |
| Ciprofloxacin |
Mexiletine |
Rifampin |
| Enoxacin |
Mibefradil |
Ropinirole |
| Fluphenazine |
Nelfinavir |
Sparfloxacin |
| Flutamide |
Norfloxacin |
Tacrine |
| Fluvoxamine |
Ofloxacin |
Ticlopidine |
| Grapefruit juice |
Oral contraceptives |
Verapamil |
| Grepafloxacin |
Perphenazine |
Zafirlukast |
Inducers of Cytochrome P-450 1A2
Inducers refers to drugs that increase the activity of a pathway.
Co-administration increases the rate of excretion for drugs metabolized through the pathway indicated, reducing the drug's effectiveness.
| Broccoli |
Chronic smoking |
Moricizine |
| Brussel spouts |
Clarithromycin |
Omeprazole |
| Cabbage |
Erythromycin |
Phenobarbital |
| caffeine |
Esomeprazole |
phenytoin |
| carbamazepine |
griseifulvin |
Rifampin |
| Cauliflower |
Insulin |
Ritonavir |
| Charbroiled foods |
Lansoprazole |
|
Methodology
DNA extraction/Polymerase Chain Reaction (PCR)/ Enzyme inactivation /Allele-specific primer extension / Hybridization using immobilized nucleic acid probes/ Fluorescent detection.
Laboratory specimens were analyzed using the Tag-ItTM Mutation Detection System for P450-2C9 which detects 5 nucleotide variants in a multiplex polymerase chain reaction and allele-specific primer extension format.
References
1. Chida M, Yokoi T, Fukui T, Kinoshita M, Yokota J, Kamataki T. Detection of three genetic polymorphisms in the 5'-flanking region and intron 1 of human CYP1A2 in the Japanese population. Jpn J Cancer Res. 1999 Sep;90(9):899-902
2. Basile VS, Masellis M, Potkin SG, Kennedy JL.Pharmacogenomics in schizophrenia: the quest for individualized therapy. Hum Mol Genet. 2002 Oct 1;11(20):2517-30
3. Cozza KL, Armstrong SC, Oesterheld JR (2003) Drug Interaction principles for Medical Practice. American Psychiatric Publishing Inc
4. Eap CB, Bender S, Sirot EJ, Cucchia G, Jonzier-Perey M, Baumann P, Allorge D, Broly F. Nonresponse to clozapine and ultrarapid CYP1A2 activity: clinical data and analysis of CYP1A2 gene. Clin Psychopharmacol. 2004 Apr;24(2):214-9
5. Eleni Aklillu, Juan Antonio Carrillo, Eyasu Makonnen, Karin Hellman, Marià Pitarque, Leif Bertilsson, and Magnus Ingelman-Sundberg. Genetic Polymorphism of CYP1A2 in Ethiopians Affecting Induction and Expression: Characterization of Novel Haplotypes with Single-Nucleotide Polymorphisms in Intron 1. 2003 Mol Pharmacol 64:659-669
6. Faber MS, Fuhr U. Time response of cytochrome P450 1A2 activity on cessation of heavy smoking. Clin Pharmacol Ther. 2004 Aug;76(2):178-84.
7. Granfors MT, Backman JT, Neuvonen M, Neuvonen PJ. Ciprofloxacin greatly increases concentrations and hypotensive effect of tizanidine by inhibiting its cytochrome P450 1A2-mediated presystemic metabolism. Clin Pharmacol Ther. 2004 Dec;76(6):598-606
8. Hamdy SI, Hiratsuka M, Narahara K, Endo N, El-Enany M, Moursi N, Ahmed MS, Mizugaki M. Genotyping of four genetic polymorphisms in the CYP1A2 gene in the Egyptian population. Br J Clin Pharmacol. 2003 Mar;55(3):321-4
9. Hong CC, Tang BK, Hammond GL, Tritchler D, Yaffe M, Boyd NF. Cytochrome P450 1A2 (CYP1A2) activity and risk factors for breast cancer: a cross-sectional study. Breast Cancer Res. 2004;6(4):R352-65. Epub 2004 May 07
10. Lewis DF, Lake BG, Dickins M. Substrates of human cytochromes P450 from families CYP1 and CYP2: analysis of enzyme selectivity and metabolism. Drug Metabol Drug Interact. 2004;20(3):111-42.
11. Nakajima M, Yokoi T, Mizutani M, Kinoshita M, Funayama M, Kamataki T. Genetic polymorphism in the 5'-flanking region of human CYP1A2 gene: effect on the CYP1A2 inducibility in humans. J Biochem (Tokyo). 1999 Apr;125(4):803-8
12. Sachse C, Brockmoller J, Bauer S, Roots I. Functional significance of a C-->A polymorphism in intron 1 of the cytochrome P450 CYP1A2 gene tested with caffeine. Br J Clin Pharmacol. 1999 Apr;47(4):445-9
13. Solus JF, Arietta BJ, Harris JR, Sexton DP, Steward JQ, McMunn C, Ihrie P, Mehall JM, Edwards TL, Dawson EP. Genetic variation in eleven phase I drug metabolism genes in an ethnically diverse population. Pharmacogenomics. 2004 Oct;5(7):895-931.
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