Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
Catechol-O-methyltransferase (COMT) is involved in phase II (conjugative) metabolism of catecholamines and catechol drugs, such as dopamine, as well as the catechol-estrogens. COMT transfers a donor methyl-group from S-adenosylmethionine to acceptor hydroxy groups on catechol structures (aromatic ring structures with vicinal hydroxy-groups).(1) Bioactive catecholamine metabolites are metabolized by COMT in conjunction with monoamine oxidase (MAO):
-Norepinephrine is methylated by COMT forming normetanephrine.
-Epinephrine is methylated by COMT forming metanephrine.
-Dopamine is converted to homovanillic acid through the combined action of MAO and COMT.
Parkinsonism patients receiving levodopa (L-DOPA) therapy are frequently also prescribed a COMT inhibitor to minimize metabolism of L-DOPA by COMT, thereby prolonging L-DOPA action.
COMT is also involved in the inactivation of estrogens. Estradiol can be hydroxylated forming the catechol estrogens 2-hydroxyestradiol and 4-hydroxyestradiol.(2) These hydroxylated estradiols are methylated by COMT, forming the corresponding methoxyestradiols. Several studies have indicated the increased risk of breast cancer due to low activity COMT.(3)
The gene encoding COMT is transcribed from alternative promoters to produce 2 forms of the enzyme, a soluble short form of the enzyme and a membrane-bound long form. Functional polymorphisms have been identified in the gene encoding COMT that lead to high- and low-activity forms of the enzyme.(4) These functional polymorphisms are designated by the position of the amino acid change in both the short and long form of the enzyme. A single nucleotide polymorphism in exon 4 of the gene produces an amino acid change from valine to methionine (Val108/158Met). This polymorphism, COMT*2, reduces the maximum activity of the variant enzyme by 25% and also results in significantly less immunoreactive COMT protein, resulting in a 3-fold to 4-fold decrease in activity compared to wild type *1. A second functional polymorphism has been identified in exon 4 that results in a threonine substitution for alanine (Ala52/102Thr). This polymorphism, COMT*3, reduces the maximum activity of the variant enzyme by 40% compared to the wild-type enzyme. The COMT*2 polymorphism has been linked to prefrontal cortex cognitive response to antipsychotic medications. Schizophrenia patients homozygous for the *2 polymorphism displayed improved cognition following drug treatment. Patients homozygous for *1 did not have improved cognition following treatment.(6)
Early identification of patients who may show cognitive improvement with treatment for schizophrenia, this is associated with the *2/*2 genotype
Investigation of inhibitor dosing for decreasing L-DOPA metabolism
Research use for assessing estrogen metabolism
An interpretive report will be provided. The normal genotype (wild type) for COMT is *1/*1. Other genotypes that lead to reduced activity alleles include COMT*2 (Val108/158Met) and COMT*3 (Ala52/102Thr).
The following information outlines the relationship between polymorphisms detected in this assay and the effect on the activity of the enzyme produced by that allele:
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Amino Acid Change
Effect on Enzyme Activity/Metabolism
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
Patients who have received a heterologous blood transfusion within the preceding 6 weeks, or who have received an allogeneic blood or marrow transplant, can have inaccurate genetic test results due to presence of donor DNA.
Catechol-O-methyltransferase (COMT) genetic test results in patients who have undergone liver transplantation may not accurately reflect the patient's COMT status.
This test does not detect polymorphisms other than those listed. Mutations in primer binding may affect test results and ultimately the genotyping calls made.
This test should not be ordered for pheochromocytoma or paragangliomas assessment. METAF / Metanephrines, Fractionated, 24 Hour, Urine; PMET / Metanephrines, Fractionated, Free, Plasma; CATU / Catecholamine Fractionation, Free, 24 Hour, Urine; or CATP / Catecholamine Fractionation, Plasma, Free should be ordered instead.
Absence of a detectable gene mutation or polymorphism does not rule out the possibility that a patient has an intermediate or poor metabolizer phenotype. Patients with an extensive or intermediate metabolizer genotype may have COMT enzyme activity inhibited by a variety of medications, or their metabolites. The following is a partial listing of drugs known to affect COMT activity.
Drugs that undergo metabolism by COMT:
Coadministration may decrease the rate of elimination of other drugs metabolized by COMT.
Drugs that undergo structural modification but are not metabolized by COMT:
Coadministration will not decrease the rate of elimination metabolism of other drugs metabolized by COMT.
Drugs known to inhibit COMT activity:
Dietary Components that inhibit COMT activity:
Coadministration will decrease the rate of metabolism of COMT metabolized drugs, increasing the possibility of toxicity, including in heterozygous individuals.
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. Weinshilboum RM, Otterness DM, Szumlanski CL: Methylation pharmacogenetics: catechol O-methyltransferase, thiopurine methyltransferase, and histamine N-methyltransferase. Ann Rev Pharmacol Toxicol 1999;39:19-52
2. Zhu BT, Conney AH: Functional role of estrogen metabolism in target cells: review and perspectives. Carcinogenesis 1998;19:1-27
3. Worda C, Sator MO, Schneeberger C, et al: Influence of the catechol-O-methyltransferase (COMT) codon 158 polymorphism on estrogen levels in women. Hum Reproduct 2003 Feb 18(2):262-266
4. Shield AJ, Thomae BA, Eckloff BW, et al: Human catechol-O-methyltransferase genetic variation: gene resequencing and functional characterization of variant allozymes. Mol Psychiatry 2004 February;9(2):151-160
5. van Duursen MBM, Sanderson JT, de Jong PC, et al: Phytochemicals inhibit catechol-O-methyltransferase activity in cytosolic fractions from healthy human mammary tissues; Implications for catechol estrogen-induced DNA damage. Toxicol Sci 2004;81:316-324
6. Weickert TW, Goldberg TE, Mishara A, et al: Catechol-O-methyltransferase val108/158met genotype predicts working memory response to antipsychotic medications. Psychiatry 2004 Nov 1;56(9):677-682