Xenobiotic Effects on COMT

A xenobiotic is a foreign chemical substance found within an organism that is not normally, naturally produced by or expected to be present within that organism. It can also cover substances which are present in much higher concentrations than are usual.41_SchemaRTS_Eng

  • In humans, 2-Oh and 4-Ohestradiol (catechol estrogens) are rapidly O-methylated to form monomethyl ethers catalyzed by COMT and S-adenosyl-L-methionine.

  • Xenobiotics may strongly inhibit COMT-mediated
    O-methylation of catechol estrogens by xenobiotics and may facilitate the development of estrogen-induced tumors.

  • Xenobiotics may therefore deplete intermediates in the Folate cycle.  Environmental burden of Xenobiotics may create a higher need for methylation support.

Catechol-O-methyl_transferase_baucom-instituteAbstract: COMT genotype, micronutrients in the folate metabolic pathway and breast cancer risk - Goodman JE, Lavigne JA, Wu K, Helzlsouer KJ, Strickland PT, Selhub J, Yager JD; Department of Environmental Health Sciences, Johns Hopkins University, Bloomberg School of Public Health, Baltimore, MD 21205, USA.

  • Catechol-O-methyltransferase (COMT) catalyzes the O-methylation of catechol estrogens (CEs), using S-adenosylmethionine (SAM) as a methyl donor.

  • Several studies have indicated that the val108met COMT polymorphism, which results in a 3-4-fold decrease in activity, is associated with increased breast cancer risk.

  • Folate, whose intake levels have also been associated with breast cancer risk, and other micronutrients in the folate metabolic pathway influence levels of SAM and S-adenosylhomocysteine (SAH), a COMT inhibitor generated by the demethylation of SAM.

  • Because these micronutrients have been shown to alter SAM and SAH levels, we hypothesized that they could also affect COMT-catalyzed CE methylation.

  • Although measurements of SAM and SAH were not initially collected, a secondary analysis of data from two nested case-control studies was performed to examine whether serum levels of folate, vitamin B12 (B12), pyridoxal 5′-phosphate (PLP), cysteine and homocysteine, in conjunction with COMT genotype, were associated with breast cancer risk. COMT(HH) (high activity COMT homozygote) breast cancer cases had statistically significantly lower levels of homocysteine (P = 0.05) and cysteine (P = 0.04) and higher levels of PLP (P = 0.02) than COMT(HH) controls. In contrast, COMT(LL) (low activity COMT homozygote) cases had higher levels of homocysteine than COMT(LL) controls (P = 0.05).

  • No associations were seen between B12, COMT genotype, and breast cancer risk. An increasing number of COMT(L) alleles was significantly associated with increased breast cancer risk in women with below median levels of folate (P(trend) = 0.05) or above median levels of homocysteine (P(trend) = 0.02). These findings are consistent with a role for certain folate pathway micronutrients in mediating the association between COMT genotype and breast cancer risk.

These findings are consistent with a role for certain folate pathway micronutrients in mediating the association between COMT genotype and breast cancer risk.

Case Study: Susan

  • 49 yo CF recent dx of Stage II Breast Ca hormone Rec +,s/p partial mastectomy, body-case-study-baucom-instituteradiation, irregular periods, shingles, intolerant of Fereston due to Headaches, constipated.  Hx of fibroids, heavy periods, fibrocystic breast. G2P2

  • nl vitals,   Estradiol 26.8pg/ml (0-32.2 menopause range)

  • Sed rate 22 (0-20)

  • Cbc, chem, thyroid panel cholesterol wnl

  • Vit D 153 (30-100)

  • GGT 15   Uric Acid 3.2

  • Glutathione 992

  • MTHFR C677+/A1298C+

  • Cytokine: base Il-6++, IL-17+, IL-12–,IFN gamma ++, TNF-a ++, IL-4++, IL-5–, IL-10++, IL-8++, G-CSF++

How would you approach treatment of this patient?

Spectracell-Methylation-Susan-Baucom-Institute

Catechol-O-Methyltransferase

Spectracell Methylation Presentation.pptx

 

  • Involved in phase II metabolism of hydroxy-estradiols
  • Involved in metabolism of xenobiotics
  • Involved in metabolism of chocolate
  • Involved in metabolism of caffeine by-products (catechins)
  • Involved in metabolism of excitatory neurotransmitters

Spectracell Methylation Presentation.pptx (1)

  • S-adenosylmethionine and magnesium dependent
  • Linked to estrogen
  • imbalance disorders
  • Is involved in hyperhomocystinemia in Parkinson patients on L-dopa
  • Is linked to psychiatric disorders

Spectracell Methylation Presentation.pptx (2)

Folate Cycle Nutrients, Homocysteine, and Transsulfuration

  • Transsulfuration is the conversion of Homocysteine with the co-factors B6 and Serine to Cystathionine.

Homocysteine-Damage-Ladd-McNamara

  • Cystathionine is then converted to Cysteine which is one of the three amino acids that compose Glutathione.
  • Polymorphisms in Cysta beta-synthase may affect the rate of conversion of Cystathionine to Cysteine.
  • Cysteine is thought to be the rate limiting step in the formation of Glutathione.

glutathione-structure-baucom-institute (2)

 

What are the Effects of MTHFR?

MTHFR mutational effects include:MTHFR-DNA-Effects-Baucom-Institute

  • chronic low glutathione
  • leaky gut and food allergies
  • chronic viruses
  • high serum B12 levels
  • low serotonin and melatonin
  • high serum ferritin and HFE mutation
  • Thalassemia and hepatorenal failure
  • FSG and renal failure
  • autoimmunity frequency in women
  • chronic dysbiosis/chronic yeast infections
  • estrogen dominant cancers
  • subtype and elevated homocysteine
  • ADD/bipolar/PMS/Chronic Fatigue/Fibromylagia
  • tongue/fingernails/thin hair
  • vericose veins/spider veins
  • hypercoagulopathy/infertility
  • elevated testosterone in men/PCOS in women
  • acne, fibroids, Endometriosis, Menometorrhagia
  • depression when on OCPs
  • exacerbation of menopausal symptoms on BHRT
  • elevated uric acid and elevated ammonia levels
  • gut barrier and dysbiosis
  • CANCER
  • estrogen dominance and obesity (estrogens effects on insulin and the insulin receptor and adiponectin)

 

Methylation

Methylation can turn genes on or off.

Some nutrients affect the methylation process quite dramatically. Methylating factors like B12, B6, MD, Zinc monitor specific methylation reactions.

Methylation_DNA_Baucom_InstituteMTHFR

What is MTHFR?

  • Methylenehydrofolatereductase is an enzyme responsible for converting 5, 10- methylenetetrahydrofolate to the product: 5-methytetrahydrofolate (5-MTHF)
  • Certain mutations in the gene coding for MTHFR produce an enzyme that has reduced activity
  • Reduced activity can lead to elevated levels of homocysteine especially when folate levels are low
  • MTHRF genotyping can provide information about potential causes of elevated homocysteine and how to address it
  • 5-methyltetrahydrofolate is involved in the metabolism of folate and homocysteine
  • The product of the reaction catalyzed by MTHFR converts homocysteine (a potentially toxic amino acid) to methionine (a useful and necessary amino acid)