COMT

The COMT gene codes for catechol-O-methyltransferase (COMT). COMT is an enzyme that helps transfer methyl groups from one compound to another [R]. 

The addition of methyl groups to compounds is called methylation. Methylation by COMT helps break down catecholamines: a family of chemical messengers that consists of dopamine, norepinephrine, and epinephrine [R]. 

Dopamine supports cognitive function, while norepinephrine and epinephrine support the “fight-or-flight” stress response [R, R, R, R, R, R].

High levels or activity of COMT result in low catecholamine levels (due to increased breakdown). Conversely, low levels or activity of COMT result in high catecholamine levels (due to decreased breakdown). 

The most widely researched COMT polymorphism is rs4680. The ‘A’ allele at this polymorphism lowers COMT activity by roughly 4 times [R, R].

People with this low-activity variant have been nicknamed “worriers,” because they break down stress-related catecholamines more slowly and take longer to adapt to stress. However, they may have a relative advantage when it comes to their cognitive abilities [R, R, R, R].

By contrast, “warriors” are people who have high-activity COMT variants. They recover more quickly during periods of stress, but tend to have lower-than-average cognitive abilities [R, R, R, R, R, R, R].

The COMT gene provides instructions for making an enzyme called catechol-O-methyltransferase. Two versions of this enzyme are made from the gene. The longer form, called membrane-bound catechol-O-methyltransferase (MB-COMT), is chiefly produced by nerve cells in the brain. Other tissues, including the liver, kidneys, and blood, produce a shorter form of the enzyme called soluble catechol-O-methyltransferase (S-COMT). This form of the enzyme helps control the levels of certain hormones.

In the brain, catechol-O-methyltransferase helps break down certain chemical messengers called neurotransmitters. These chemicals conduct signals from one nerve cell to another. Catechol-O-methyltransferase is particularly important in an area at the front of the brain called the prefrontal cortex, which organizes and coordinates information from other parts of the brain. This region is involved with personality, planning, inhibition of behaviors, abstract thinking, emotion, and working (short-term) memory. To function efficiently, the prefrontal cortex requires signaling by neurotransmitters such as dopamine and norepinephrine. Catechol-O-methyltransferase helps maintain appropriate levels of these neurotransmitters in this part of the brain.

Read: COMT: Function & Health Implications of a Dopamine Gene

COMT and Methylation

Catechol-O-Methyltransferase is an enzyme that transfers methyl groups. COMT introduces a methyl group to catecholamines (dopamine, epinephrine, and norepinephrine), which is donated by S-adenosylmethionine (SAM) (R).  

Therefore, you need adequate SAM for COMT to work. Having too little SAM and too much SAH (s-adenosylhomocysteine) from undermethylation results in COMT inhibition as well (R).

For this reason, MTHFR SNPs that cause undermethylation and COMT SNPs that lower COMT levels are a bad combination (R).

COMT gene production is itself influenced by methylation (R).  

Usually, methylation shuts down gene production.

Supplements and COMT

Any compound having a catechol structure, like catechol estrogens and catechol-containing flavonoids, are targets of COMT (R) and are also capable of inhibiting enzyme function (either directly or through competition) (R). Such flavonoids that are modified by COMT and also inhibit/compete with COMT include Quercetin (R), Rutin, Luteolin (R), EGCG (R), Catechins, Epicatechins, Fisetin (R), Ferulic acid, and Hydroxytyrosol, (R, R2). L-dopa also is modified and competes for COMT (R).

Reactions By COMT

Specific reactions catalyzed by COMT include:

• Dopamine ’ 3-Methoxytyramine

• DOPAC ’ HVA (homovanillic acid)

• Norepinephrine ’ Normetanephrine

• Epinephrine ’ Metanephrine

• Dihydroxyphenylethylene glycol (DOPEG) ’ Methoxyhydroxyphenylglycol (MOPEG)

• 3,4-Dihydroxymandelic acid (DOMA) ’ Vanillylmandelic acid (VMA)

COMT and Gender Effects

COMT is decreased by estrogen (R), such that overall COMT activity in prefrontal cortex and other tissues is about 30% lower in females than in males (R).

This diminished COMT activity translates to about 30% higher baseline Dopamine levels in females than males (R). Females have near optimal levels of baseline dopamine levels, but males having somewhat too low baseline dopamine, such that male performance improves when dopamine levels are slightly increased, whereas female performance does not.

Therefore, having SNPs that result in lower COMT (such as the A allele for rs4680) will be more helpful for males, but not females.  Indeed, males with lower COMT do, in fact, demonstrate improved performance on tasks dependent on the prefrontal cortex, whereas females do not (R).

Catechol Estrogens, Cancer and Autoimmunity (R)

Catechol estrogens form from CYP enzymes breaking down Estradiol and Estrones (R).

Catechol estrogens can break DNA and cause cancer and autoimmune conditions (R). COMT methylates (using SAM) and inactivates these catechol estrogens (2- and 4-hydroxycatechols) (R). The products of COMT methylation are 2- and 4-o-methylethers, which are less harmful and excreted in the urine (they have anti-estrogen properties) (R). However, if COMT is inhibited too much either because of genetics or dietary inhibition, it should result in higher levels of catechol estrogens, especially if glucuronidation and sulphation pathways are not working (R). 4-Hydroxyestrone/estradiol was found to be carcinogenic in the male Syrian golden hamster kidney tumor model, whereas 2-hydroxylated metabolites were without activity (R). 4-Hydroxyestrogen can be oxidized to quinone intermediates that react with purine base of DNA, resulting in depurination adduct that generates cancerous mutations. Quinones derived from 2-hydroxyestrogens are less toxic to our DNA (R). Estrone and estradiol are oxidized to a lesser amount to 2-hydroxycatechols by CYP3A4 in the liver and by CYP1A in extrahepatic tissues or to 4-hydroxycatechols by CYP1B1 in extrahepatic sites, with the 2-hydroxycatechol being formed to a larger extent (R).

It has been observed that tissue concentration of 4-hydroxyestradiol is highest in malignant cancer tissue, out of all the estrogens (R).

The concentration of these Catechol Estrogens in the hypothalamus and pituitary are at least ten times higher than parent estrogens (R). Catechol Estrogens have potent endocrine effects and play an important role in hormonal regulation (those produced by hypothalamus and pituitary) (R).

Increased availability of estrogen and estradiol for binding and hypothalamic sites would facilitate the formation of Catechol Estrogens. These estrogens affect Luteinizing Hormone (LH) and maybe follicle stimulating hormone (FSH) and prolactin (R).

Catecholestradiol competes with estradiol for estrogen binding sites in the anterior pituitary gland and hypothalamus and dopamine binding sites on anterior pituitary membranes (R).

Other possible mechanisms of inactivation of these catechol estrogens include conjugation by glucuronidation and sulphation (R).

High concentration of 4-hydroxylated metabolites caused insufficient production of methyl, glucuronide or sulfate conjugate which in turn results in catechol estrogen toxicity in cells and oxidation to semiquinone and quinone, which may reduce glutathione (GSH). These oxidation products could lead to DNA mutations (R). The quinone/semiquinone redox system produces superoxide ions (O2¯ ) which can react with NO to form peroxynitrite, which could cause DNA damage (R).

In summary, CEs lead to the production of potent ROS, capable of causing DNA damage, thus playing an important role not only in causing cancer but also in systemic lupus erythematosus (SLE) and Rheumatoid Arthritis (R). The abilities of the estrogens to induce DNA mutations were ranked as follows: 4-hydroxyestrone (most damaging) > 2-hydroxyestrone > 4-hydroxyestradiol >2-hydroxyestradiol > > Estradiol, Estrone (R).

Fixes For Low COMT

If you have lower levels of COMT, the following may counteract some of the effects of the gene:

• SAM-e – however, this can increase dopamine levels in people who already have high dopamine.
• Methyl Guard Plus  to ensure adequate B6, B12, folate and betaine to support the formation of S-adenosylmethionine and prevent elevated homocysteine; S-adenosylhomocysteine inhibits COMT activity (R).
• Ensure adequate anti-oxidants to prevent oxidation of dopamine and pro-carcinogenic 4-hydroxyestrogens,
• Magnesium Citrate (magnesium is a cofactor)
• Be careful of the following supplements that are the targets of COMT: quercetin, rutin, luteolin, EGCG, catechins, Epicatechins, Fisetin, Ferulic acid, Hydroxytyrosol
• Avoid excessive alcohol consumption.  Since alcohol-induced euphoria is associated with the rapid release of dopamine in limbic areas, low activity COMT variant would have a relatively low dopamine inactivation rate, and therefore would be more vulnerable to the development of alcohol dependence (R).
• Avoid stimulants, especially amphetamines.  Amphetamines may do worse with people who are AA, but later studies did not replicate this.  It could be differences in study design (R).
• Avoid chronic stress (stress hormones require COMT for degradation and compete with estrogens),

Stay away from COMT inhibitors, which include: Quercetin (R), Rutin, Luteolin (R), EGCG (R), Catechins, Epicatechins, Fisetin (R), Ferulic acid, Hydroxytyrosol, (R, R2). Mercury is also a COMT inhibitor (R), so make sure you reduce your load or take supplements that bind to mercury.

Fixes For Higher COMT

If you have higher COMT levels:

• Mucuna  to increase dopamine,
• Tyrosine to increase dopamine,
• EGCG/Tea (COMT inhibitor),
• Epicatechins/Chocolate (COMT inhibitor),
• Luteolin