Mayo Test Catalog, (Sorted By Test Name) - Mayo Medical ...

2D6T
87966
duplication and multiduplication of the human CYP2D6 gene and methods for detection of duplicated
CYP2D6 genes. Gene 1999 Jan 21;226(2):327-338 3. Kirchheiner J, Brosen K, Dahl ML, et al: CYP2D6
and CYPSC19 genotype-based dose recommendations for antidepressants: a first step towards
subpopulation-specific dosages. Acta Psych Scand 2001 Sept;104(3):173-192 4. Lam YWF, Gaedigk A,
Ereshefsy L, et al: CYP2D6 inhibition by selective serotonin reuptake inhibitors: analysis of achievable
steady-state plasma concentrations and the effect of ultrarapid metabolism at CYP2D6. Pharmacotherapy
2002;22:1001-1006
Cytochrome P450 2D6 Genotype for Tamoxifen Hormonal
Therapy
Clinical Information: Tamoxifen is a hormonal therapy used for patients with estrogen
receptor-positive breast cancer. It is a selective estrogen receptor modulator (SERM) that exerts its
effect by binding to the estrogen receptor (ER). Tamoxifen is metabolized by the cytochrome P450
enzyme system to active metabolites. Two enzymes, cytochrome P450 3A (CYP3A) and 2D6
(CYP2D6), have been identified that are both necessary to generate 4-hydroxy-N-desmethyl-tamoxifen,
generically named endoxifen, the most active metabolite of tamoxifen.(1) Endoxifen is approximately
100 times more potent in ER binding than the parent drug, tamoxifen, or the metabolite N-desmethyl
tamoxifen.(2) CYP2D6 is an enzyme involved in the metabolism of many drugs including
antidepressants, antihypertensive medications, cardioactive drugs, and stimulants, as well as tamoxifen.
CYP2D6-mediated drug metabolism is highly variable. Some individuals have altered CYP2D6 gene
sequences that result in decreased enzyme production or production of enzyme with diminished
catalytic activity. Furthermore, the entire gene can be deleted in some individuals, resulting in absent
enzyme activity and poor metabolizer status. Breast cancer patients who receive tamoxifen and who are
CYP2D6 poor metabolizers produce suboptimal concentrations of endoxifen.(3) These patients have
poorer outcomes, with an increased risk of breast cancer recurrence, compared to CYP2D6 extensive
(normal) metabolizers.(2) Because tamoxifen metabolites exert their effect by binding to the ER, hot
flashes are a common side effect. However, patients who are CYP2D6 poor metabolizers appear to have
a much lower incidence of bothersome hot flashes, consistent with data demonstrating that these
patients have lower concentrations of the active tamoxifen metabolites. Polymorphisms associated with
CYP2D6 poor metabolizer status are autosomal recessive. Consequently, only individuals who are
homozygous or who are compound heterozygous for these polymorphisms are poor metabolizers. The
following information outlines the relationship between the polymorphisms detected in the CYP2D6
genotyping assay and the effect on the activity of the enzyme produced by that allele: Allele
Designation Nucleotide Change Effect on CYP2D6 mRNA or Protein Effect and Phenotype *1 No poly
morphisms detected Normal mRNA and protein Normal activity; predicted extensive metabolizer status
for tamoxifen. *2A -1584C->G Increased transcription *3 2549A->del Nonsense mutation No activity;
predicted poor metabolizer status for tamoxifen. *4 1846G->A mRNA splicing *5 gene deletion Entire
gene deleted *6 1707T->del Nonsense mutation *7 2935A->C Missense mutation *8 1758G-> Stop
codon *11 883G->C mRNA splicing *12 124G->A Missense mutation *14A 100C->T 1758G->A
Missense mutation *15 138insT Nonsense mutation *2 2850C->T Missense mutation Activity with
tamoxifen has not been determined; metabolizer status for tamoxifen unknown. *9 2613AGA>del
Lysine282 deletion *10 100C->T Missense mutation *14B 1758G->A Missense mutation *17
1023C->T Missense mutation *41 2988G->A mRNA splicing Gene duplications Whole gene
duplication Depends on the allele duplicated Allele duplication may result in no change in activity
(duplication of deficient alleles) or potentially increase the metabolism of tamoxifen (ultrarapid
metabolism). A complicating factor in correlating CYP2D6 genotype with phenotype is that many drugs
or their metabolites are inhibitors of CYP2D6 catalytic activity. For example, many antidepressants,
including some of the tricyclic antidepressants and some of the selective serotonin reuptake inhibitors,
especially fluoxetine and paroxetine, are particularly inhibitory to CYP2D6 activity. Other drugs that
inhibit CYP2D6 activity include some cardioactive drugs (eg, quinidine and amiodarone), some drugs
of abuse (eg, cocaine), methadone, many histamine H1 receptor antagonists (eg, cimetidine), celecoxib,
and ritonavir. Comedication with tamoxifen and inhibitory drugs may produce a CYP2D6 poor
metabolizer phenotype, even though the patient has a CYP2D6 genotype consistent with intermediate or
extensive metabolism. Consequently, it is important to interpret the results of CYP2D6 genotype testing
in the context of coadministered drugs. Because antidepressants are often prescribed to alleviate the hot
Current as of January 3, 2013 2:22 pm CST 800-533-1710 or 507-266-5700 or MayoMedicalLaboratories.com Page 585