Archive for the ‘Epigenetics’ Category

How do we access and arrest poor methylation in the body?

Wednesday, September 14th, 2011

We follow up our discussion on the epigenetic mechanisms that affect gene expression that are asserted by dietary intake, environment toxins and aging. In particular, we mentioned the importance of methylation. Today, I would like to discuss how we could access methylation status in the body and what could be done to prevent hypomethylation. Methylation is important for gene expression and repair. Methylation of proteins is equally important in the synthesis of neurotransmitter and phospholipids. Hypomethylation increases expression of certain promoter genes and could trigger oncogenesis. DNA methylation is established during embryonic development and is stable through multiple cell divisions (cellular memory). It is normally associated with gene silencing.  It targets the Cytosine-Guanine dinucleotides and up to 70% are methylated in human somatic cells. The CG islands that are located adjacent to suppressor genes are however hypomethylated to allow for expression of these suppressor genes. Hypermethylation in the CPG islands are seen in certain tumor types.

Poor methylation has been implicated in degenerative brain disorders such as Alzheimer’s disease and Parkinson’s disease, depression, autism and ADHD, cancers, arthritis and CVS diseases.

What governs the methylation process in the body? {{{0}}}

There are 3 critical steps in the methylation process:

  1. The primary carrier of the methyl group is the amino acid, methionine. It delivers the methyl group via SAME, S-adenosylmethionine which requires ATP.
  2. Methionine is formed from homocysteine accepting the methyl group from the single carbon pool via its final methyl tetrahydrofolate facilitate by vitamin B12
  3. The single carbon pool is contributed mainly by amino acids such as serine, glycine, histidine and tryptophan that needs the critical vitamin Folate. The pool of methylene-THF, methenyl THF and formyl THF is reversible but the final step to 5 methyl THF is a committed and irreversible step. Therefore, the buildup of methy THF would be “trapped” if vitamin B12 is not available to allow its transfer to homocysteine to methionine, a process known as the “Folate Trap”. If a patient is deficient in both B12 and folate but only takes folic acid supplements, the B12 deficiency may be masked. In such cases, the anemia associated with both may be resolved, but the underlying neuropathy of vitamin B12 will persist.
The methylation process is inhibited by oxidative stress in favour of another important process of converting homocysteine to important antioxidants such as glutathione and the sulphur containing amino acids such as taurine and sulphate which are also key in supporting phase II detoxification in the liver.

How do we access methylation in the body?

  1. Homocysteine – elevated levels suggest a blockage in methylation. Homocysteine has been investigated as a separate risk factor for coronary heart disease. It has been postulated as a putative factor in endothelial dysfunction and arteriosclerosis. It is also a very useful marker for poor methylation.
  2. The Critical Vitamins – Folate for the single carbon pool formation from the mentioned amino acids and vitamin B12 for the formation of methionine from homocysteine. While serum folate and B12 could be measured, there are more sensitive tests using urinary organix that are metabolites of folate and Vit B12 – FLGLU (formiminoglutamate) and methylmalonate respectively. The latter is present in the urine as short as 10 days of vitamin B12 deficiency.
  3. Measures of serum amino acids contributing to the single carbon pool such as serine, glycine, histidine and tryptophan are also useful in determining the methylation status.

What could we do to improve methylation status in the body?

  1. Ensure that dietary intake of critical vitamins such as folate and vitamin B12 is sufficient – this is especially so in patients who are pregnant or alcoholics and those with pernicious anemia or on prolonged antacids or PPI or H2 antagonists that reduce stomach acid that could affect absorption of vitamin B12. Adequate intake of the amino acids such as the single carbon pool precursors is also important especially in aged patients.
  2. Supplements such as SAM-e , the active compound for methylation. Caution is needed in patients who are taking antidepressants such as MAOI or SSRIs.

The clinical implications of the methylation status in the body have yet been fully investigated. We know of its importance in gene expression and repair but how does this translate to clinical benefits and well being has yet been fully investigated and validated in clinical studies. There is little incentive for such studies as there is little financial return expected since the solution is simple vitamin and dietary adjustments that are not patentable and thus is of little interest to the pharmaceutical industry. However, it is only prudent to ensure that the body is not at risk of poor gene repair and expression due to simple risk-free dietary measures that could be taken to ensure good methylation.  I would certainly advocate such dietary adjustment particularly if lab tests confirmed poor methylation status such as elevated homocysteine, urinary FIGLU and methylmalonate and low serum amino acids important in maintaining the single carbon pool.