Conjugation of Toxins and Elimination: large water-soluble molecules are added to toxins, usually at the reactive site formed by Phase I reactions. After Phase II modifications, the body is able to eliminate the transformed toxins in the urine or the feces (through the bile).

All Polymophisms which Genovations tested for are mentioned in the following list:

• COMT
• NAT
• GST
• SOD

COMT (Gene makes the Catechol-O-methyl transferase enzyme) location V158M

Functions:

• Methylation, in the liver & gut
• primarily responsible for breaking down the neurotransmitters dopamine, epinephrine, and norepinephrine
• inactivates catecholamines, catechol estrogens, and catechol drugs such as L-DOPA

My Results: SNP detected on one of the two chromosomes.

Clinical Implications of COMT SNP:

• Polymorphism results in reduced COMT activity, thus decreased degradation of substrates.
  • Impaired estrogen metabolism, including...
    • Individuals carrying the M alleles (+)
      • have a 4-fold reduced clearance of dopamine, epinephrine and norepinephrine from neural synapses.
      • if taking Estrogen replacement therapy, may experience higher estrogen levels than expected
      • Breast cancer risk is increased with long-term estrogen replacement and in women who also have a GST polymorphism (as I do).
      • Genovations doesn't mention other problems with estrogen metabolism, but I have experience with some. See "For more information, below.
  • Due to higher amounts of synaptic dopamine, the polymorphism is associated with
    • improved cognition
    • decreased risk of schizophrenia
    • increased risk for some other neuropsychiatric disorders, including
      • depression
      • ADHD
      • anxiety and ultra rapid cycling bipolar
      • disorder
      • anti-social behavior
      • increased sensitivity to pain
      • fibromyalgia
      • migraine
      • late-onset alcoholism
      • possibly Parkinsons disease.
  • Homozygous positive bipolar patients may develop rapid cycling with methylphenidate (Ritalin).

Minimizing Risks from COMT SNP:

• Avoid excessive alcohol consumption; seek help if alcohol consumption is a health issue.
• Minimize sustained mental and environmental stress (stress hormones require COMT for degradation and compete with estrogens).
• Ensure adequate intake of B vitamins, magnesium, and amino acids.
• Avoid high homocysteine (S-adenosylhomocysteine inhibits COMT)
• Antioxidants to prevent oxidation of pro-carcinogenic 4-hydroxyestrogens.
• Use caution with
  • amphetamine-based medications
  • catechol drugs.
  • methylphenidate (Ritalin).
• Consider carefully the increased risk from Estrogen replacement therapy.
• Don't use quercetin: Inhibition of Catechol O-Methyltransferase-catalyzed O-Methylation of 2- and 4-Hydroxyestradiol by Quercetin. Bao Ting Zhu, Joachim G. Liehr.

NAT (N-acetyl transferase enzymes)

Function: Acetylation

• N-acetyltransferase 1 is found in extra-hepatic tissues
• N-acetyltransferase 2 is found predominantly in the liver and the gut. NAT2 acetylates numerous environmental toxins, including
• • heterocyclic aromatic amines.
  • tobacco smoke
  • exhaust fumes.
• Both NAT1 and NAT2 are used in the acetylation of numerous environmental toxins, including heterocyclic aromatic amines.

Slow Metabolizer NAT Polymorphism

• Gene NAT1, location R64W
  • affects all cells
  • My results: no polymorphism found
• Gene NAT1, location R187Q
  • In the liver and gut
  • My results: no polymorphism found
• Gene NAT2, location I114T
  • In the liver and gut
  • My results: polymorphism found on one of the two chromosomes
• Gene NAT2, location R197Q
  • In the liver & gut
  • My results: polymorphism found on one of the two chromosomes
• Gene NAT2, location G286E
  • In the liver and gut
  • My results: no polymorphism found
• Gene NAT2, location R64Q
  • In the liver and gut
  • My results: no polymorphism found

Fast Metabolizer NAT Polymorphism

• Gene NAT2, location K268R
  • In the liver and gut
  • My results: polymorphism found on one of the two chromosomes

Health Implications of NAT SNPs:

• Polymorphisms can result in slower than normal or faster than normal addition of an acetyl group to these toxins.
• Slow acetylators
  • poor clearing of toxins
  • the resulting increased total toxic burden can increase the risk of lung, colon, breast, bladder, or head & neck cancer.
  • Urinary cancer appears to have the most consistent association with slow acetylation.
• Rapid acetylators
  • add acetyl groups so rapidly that they make mistakes in the process
  • increase 0-acetylation of toxins that can actually make the toxins more reactive.
• Colon cancer appears to have the most consistently reproducible association with fast acetylation.
• Both slow and rapid acetylators are at increased risk for toxic overload if they are exposed to environmental toxins.

Minimizing Risk from NAT SNPs:

• If you smoke, stop. Your risk of lung and breast cancer is substantially higher than someone with normal NAT activity.
• Do not eat fried foods and minimize red meat as these substantially increase your risk of colorectal cancer.
• Avoid well-done meats as these may substantially increase your risk of breast cancer.
• Foods that increase acetylation: most vegetables and fruits but especially
  • cruciferous (cabbage-family) vegetables
  • garlic, onions
  • soy
  • grapes and berries

GST (Glutathione s-transferase enzymes)

Functions:

• The GST isoforms (M1, P1, and T1) act similarly but predominate in various tissues.
• All catalyze the conjugation of electrophilic and water-soluble compounds with glutathione.
• For more information see Glutathione Metabolism - Functions.

My results:

• Gene GSTM1, location 1p13.3
  • In the liver and kidney
  • Test indicates that the gene is present; lab was unable to determine whether on one or both chromosomes.
• Gene GSTP1, location I105V
  • In the brain and skin
  • Polymorphism found on both of the two chromosomes
• Gene GSTP1, location A114V
  • In the brain and skin
  • Polymorphism found on one of the two chromosomes.

Health implications of defects in GST activity:

• May increase
  • toxic burden
  • oxidative stress.
  • risk of
    • fatigue syndromes
    • various cancers,
      • particularly malignant melanoma, as well as Hodgkin's and non-Hodgkins lymphomas.
      • throughout the body, particularly in lung, prostate, head & neck.
• GST polymorphisms should be seen as disease-modifying rather than disease-causing, likely via their role in cellular protection against cellular oxidative stress -- a risk that appears to be additive with increasing numbers of polymorphisms to various isozymes.
• GST polymporphisms generally indicate a poorer prognosis in
  • Chronic diseases, for example multiple sclerosis and cystic fibrosis
  • Cancer. In particular, ovarian cancer and malignant melanoma do not respond well to chemotherapy.

Minimizing Risk from GST defects:

• Regardless of genotype, increasing the body's production of glutathione will reduce oxidative stress and afford greater protection against a wide array of toxins. (But for people like me who have trouble metabolizing cysteine, this can be problematic. See My Glutathione Experience.)
• Avoid substances requiring GSH to detox:
• • Cigarette smoke
  • herbicides, fungicides, insect sprays, industrial solvents.
• Ginkgo biloba boosts GST -- in mice, anyway: see Studies on the constituents of edible and medicinal plants. 41. Effects of Ginkgo biloba and its terpene constituents on phase II drug-metabolizing enzymes and glutathione levels in mouse liver. Sasaki Keiko, Wada Keiji, and Haga Masanobu.
• Glutathione Supplementation.

SOD (Superoxide Dismutase enzymes)

Functions:

• Oxidative protection: converts reactive oxygen species into less reactive hydrogen peroxide.
• Protects cells from increased oxidative stress and free radical damage to cell structures like membranes, mitochondria, DNA, and proteins.
• SOD1 is present in the cytosol
• SOD2 is present in the mitochondria (where most of the body's energy is made) -- the primary anti-oxidant enzyme there

My SOD Results:

• Gene SOD1, location G93A
  • In the Cytosol
  • No polymorphisms found
• Gene SOD1, location A4V
  • In the Cytosol
  • No polymorphisms found
• Gene SOD2, location A16V
  • In the Mitochondria
  • Polymorphisms found on both chromosomes

Health Implications of Polymorphisms in SOD enzymes:

• Changes in the SOD enzyme are associated with higher risk of
  • oxidative stress and related conditions
  • neurodegenerative disorders like ALS.
• This genotype has specifically been associated with cardiomyopathy.

Minimizing Risk from SOD Polymorphism:

• Colorful vegetables and fruits
  • for example, banana - see Antioxidant activity of banana flavonoids. Vijayakumar S, Presannakumar G, Vijayalakshmi NR.:"The antioxidant activity of flavonoids from banana (Musa paradisiaca) was studied in rats fed normal as well as high fat diets. Concentrations of peroxidation products namely malondialdehyde, hydroperoxides and conjugated diens were significantly decreased whereas the activities of catalase and superoxide dismutase were enhanced significantly. Concentrations of glutathione were also elevated in the treated animals."
• Broad-spectrum anti-oxidant supplements, including agents that help to raise glutathione levels --e.g.
  • vitamin C
  • magnesium
  • n-acetylcysteine (NAC)
  • alpha-lipoic acid
  • milk thistle
• Manganese (a cofactor for SOD2) may also be helpful.