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1A2O
60346
Cytochrome P450 1A2 Genotype, Saliva
Clinical Information: Primary metabolism of many drugs is performed by cytochrome P450
(CYP), a group of oxidative/dealkylating enzymes localized in the microsomes of many tissues
including the intestines and liver. One of these CYP enzymes, CYP1A2, is wholly or partially
responsible for the hydroxylation or dealkylation of many commonly prescribed drugs (see below). The
current clinical application of this test is focused on the impact of allelic variation on antidepressant and
antipsychotic metabolism. CYP1A2-mediated drug metabolism is highly variable. CYP1A2*1A is the
wild type or normal allele. Some individuals have altered CYP1A2 gene sequences that result in
synthesis defective enzyme. These individuals metabolize CYP1A2 substrates poorly. Changes in the
promoter impacting gene induction of the CYP1A2 gene has been observed, which results in either an
increase or decrease of overall metabolic activity. Dosing of drugs that are metabolized through
CYP1A2 may require adjustment based on the individual patient's genotype. Patients who are poor
metabolizers may require lower than usual doses to achieve optimal response. Patients who are
ultrarapid metabolizers may benefit from increased doses. Patients with either ultrarapid or poor
metabolism also may benefit by conversion to other comparable drugs that are not primarily
metabolized by CYP1A2. A number of specific polymorphisms have been found in the CYP1A2 gene
that results in enzymatic deficiencies. The frequency of these polymorphisms varies within the major
ethnic groups. All of the identified polymorphisms associated with CYP1A2 are autosomal recessive.
Consequently, only individuals who are homozygous or compound heterozygous for these
polymorphisms are poor metabolizers. Individuals who are heterozygous, with 1 normal gene and 1
defective polymorphic gene, will have metabolism intermediate between the extensive (normal) and
poor metabolizers. The following information outlines the relationship between the polymorphisms
detected in this assay and the effect on the activity of the enzyme produced by that allele: Nucleotide
Change Effect on Enzyme Metabolism* -3860G->A Lower inducibility in Asians but increased
inducibility in Northern Europeans -2467T->del T Increased inducibility -729C->T Decreased activity
and decreased inducibility -163C->A Increased inducibility 125C->G Greatly reduced activity 558C->A
Greatly reduced activity 2116G->A Decreased activity 2385G->A Decreased activity 2473G->A
Greatly reduced activity 2499A->T Decreased activity 3497G->A Decreased activity 3533G->A No
activity 5090C->T Greatly reduced activity 5166G->A Decreased activity *Effect of a specific
polymorphism on the activity of the CYP1A2 enzyme can only be estimated since the literature does not
provide precise data. A complicating factor in correlating CYP1A2 genotype with phenotype is that
some drugs or their metabolites are inhibitors of CYP1A2 catalytic activity. These drugs may reduce
CYP1A2 catalytic activity. Consequently, an individual may require a dosing decrease greater than
predicted based upon genotype alone. Another complicating factor is that the CYP1A2 gene is inducible
by several drugs and environmental agents (eg, cigarette smoke) and the degree of inducibility is under
genetic control. It is important to interpret the results of testing in the context of other coadministered
drugs and environmental factors.
Useful For: Identifying patients who are poor, intermediate, extensive, or ultrarapid metabolizers of
drugs metabolized by CYP1A2 Adjusting dosages for drugs that are metabolized by CYP1A2
Interpretation: An interpretive report will be provided that includes assay information, genotype,
and an interpretation indicating whether results are consistent with a poor, intermediate, extensive, or
ultra-rapid metabolizer phenotype. The report will list drugs known to affect metabolism by CYP1A2.
Direct polymorphism analysis for -3860G->A, -2467T->del T, -729C->T, -163C->A, 125C->G,
558C->A, 2116G->A, 2385G->A, 2473G->A, 2499A->T, 3497G->A, 3533G->A, 5090C->T, or
5166G->A is performed following PCR amplification. Direct DNA testing will not detect all the known
mutations that result in decreased or inactive CYP1A2 alleles. This assay does not test for some known
polymorphisms because those polymorphisms have not been associated with alterations in enzymatic
activity. Rare or undescribed variants may not have been found during validation but will be sequence
verified upon detection. See http:///www.cypalleles.ki.se/cyp1a2.html for a full description of CYP1A2
alleles. Absence of a detectable gene mutation or polymorphism does not rule out the possibility that a
patient has a metabolizer status other than predicted above. The frequency of polymorphisms causing
poor metabolism has not been fully characterized in various ethnic groups. Patients with an ultrarapid,
extensive, or intermediate genotype may have CYP1A2 enzyme activity inhibited or induced by a
variety of substances, medications, or their metabolites. The following is a listing of substances known
Current as of January 3, 2013 2:22 pm CST 800-533-1710 or 507-266-5700 or MayoMedicalLaboratories.com Page 577