Glutathione depletion blocks conversion of OH-B12 to methyl-B12

Discussion in 'Fibromyalgia Main Forum' started by richvank, Aug 12, 2011.

  1. richvank

    richvank New Member

    Glutathione depletion blocks conversion of OH-B12 to methyl-B12: new evidence

    Hi, all.

    Will Marsden recently called my attention to a recent paper from Prof. Richard Deth's group (abstract below) that provides evidence from a rat experiment that major glutathione depletion blocks the conversion of hydroxocobalamin to methylcobalamin.

    This has been one of the main propositions of the pathogenesis model that I have proposed for ME/CFS, i.e. the Glutathione Depletion--Methylation Cycle Block hypothesis. So far, this model has continued to be supported as more research is being completed.

    One of the things this has brought home to me is that in cases in which glutathione or SAMe are extremely low, it will be difficult to get the methylation cycle going using hydroxocobalamin as the form of B12. This is the form included in the simplified protocol I have suggested, and it was found to be helpful for more than two-thirds of the people in our clinical study, but this may explain why some of the people did not receive benefit from this protocol.

    Note that the protocol recommended by Freddd uses methylcobalamin as one of the forms of B12. Methylcobalamin is also used by Dr. Amy Yasko in some cases, depending on genomic polymorphisms. It is also used by Dr. Neubrander and other physicians participating in the DAN! project for treating autism.

    Recently I have been suggesting that if the simplified protocol does not produce benefits within three months, either testing should be performed to determine why, or a change should be made in the protocol used. One possibility would be to add methylcobalamin, starting at low dosage and working up, as tolerated.

    Best regards,


    Alcohol Clin Exp Res. 2011 Feb;35(2):277-83. doi: 10.1111/j.1530-0277.2010.01343.x. Epub 2010 Dec 1.

    Ethanol lowers glutathione in rat liver and brain and inhibits methionine synthase in a cobalamin-dependent manner.

    Waly MI, Kharbanda KK, Deth RC.

    Department of Food Science and Nutrition, Sultan Qaboos University, Muscat, Sultanate of Oman.

    Methionine synthase (MS) is a ubiquitous enzyme that requires vitamin B12 (cobalamin) and 5-methyl-tetrahydrofolate for the methylation of homocysteine to methionine. Previous studies have shown that acute or chronic ethanol (ETOH) administration results in the inhibition of MS and depletion of glutathione (GSH), and it has been proposed that GSH is required for the synthesis of methylcobalamin (MeCbl).

    We measured GSH levels and investigated the ability of different cobalamin cofactors [cyano- (CNCbl), glutathionyl- (GSCbl), hydroxo- (OHCbl), and MeCbl] to support MS activity in liver and brain cortex from control and ETOH-treated rats.

    In control animals, MS activity was higher in liver than in cortex for all cobalamins and MeCbl-based activity was higher than for other cofactors. S-adenosylmethionine (SAM) was required for OHCbl, CNCbl, and GSCbl-based activity, but not for MeCbl. Feeding an ETOH-containing diet for four weeks caused a significant decrease in liver MS activity, in a cobalamin-dependent manner (OHCbl ? CNCbl > GSCbl > MeCbl). In brain cortex, OHCbl, CNCbl, and GSCbl-based activity was reduced by ETOH treatment, but MeCbl-based activity was unaffected. GSH levels were reduced by ETOH treatment in both liver and cortex homogenates, and addition of GSH restored OHCbl-based MS activity to control levels. Betaine administration had no significant effect on GSH levels or MS activity in either control or ETOH-fed groups.

    The ETOH-induced decrease in OHCbl-based MS activity is secondary to decreased GSH levels and a decreased ability to synthesize MeCbl. The ability of MeCbl to completely offset ETOH inhibition in brain cortex, but not liver, suggests tissue-specific differences in the GSH-dependent regulation of MS activity.

    Copyright © 2010 by the Research Society on Alcoholism.


    Note: This abstract was copied from PubMed, a service of the U.S. government. Abstracts on PubMed are in the public domain with respect to copyright.

  2. Scapper

    Scapper New Member

    Hi Rich: thank you for this article.

    Question: I've taken 2-3mgs of methylcobabalamin for well over 5 years now.

    What do you feel is a "therapeutic" dose?

  3. richvank

    richvank New Member

    Hi, Scapper.

    It seems to vary between people. For most PWMEs, I think 2-3 milligrams of methylcobalamin, either sublingually or by injection, would be therapeutic, if methylfolate and necessary cofactors are also taken. Some people need more B12 because of the set of genetic polymorphisms that they have inherited.

    Best regards,

  4. Mikie

    Mikie Moderator

    Thank you so much for noting that this info is in the public domain. Makes our jobs easier as mods. Also, thank you for all the good info you provide.

    Love, Mikie
  5. donnaba

    donnaba New Member

    so what does this mean for those of us with an absent GSTM1 gene on the detox profile?
  6. mbofov

    mbofov Active Member

    This is really interesting - thanks so much for posting!

  7. richvank

    richvank New Member

    Hi, donnaba.

    It is pretty common for people to have an absent GSTM1 gene. This will hinder somewhat the ability to conjugate glutathione to toxins, in order to detox them and remove them from the body. However, there are many nominally healthy people who have an absent GSTM1 gene.
    I think its effect will depend on what other polymorphisms are present in their detox genes, which will produce an additive effect with the missing GSTM1.

    For example, I have found quite a few women with ME/CFS who have polymorphisms in CYP1B1, COMT, and one or more of the GST enzymes. I have hypothesized that this combination is the reason for the higher prevalence of ME/CFS in women that in men. The reason is that this combination produces additional oxidative stress due to redox cycling when a woman's body is metabolizing estradiol. A man may also have this combination of polymorphisms, but it will not produce additional oxidative stress, because men have much lower levels of estradiol.

    Best regards,

  8. donnaba

    donnaba New Member

    thanks Rich, I have polymorphisms in the CYP2C9 andCYP3A4. And 3 of the NAT2 as well as ++ SOD2. So who knows what to make of my pattern. Is supplementing with glutathione recommended then for me? I've just read about an acetyl-glutathione which is supposed to be comparable to IV, any thoughts?;col1

    thanks, donna
  9. richvank

    richvank New Member

    Hi, Donna.

    Those polymorphisms will make it difficult for your detox system to dispose of most drugs and some environmental toxins.

    If you have ME/CFS, it is likely that you have a partial methylation cycle block. We have found that in order to raise glutathione to normal on a permanent basis, it is necessary to lift this partial block. Direct boosting of glutathione by various means gives temporary benefit to some PWMEs, while others are not able to tolerate it.

    I, too, have been hearing about acetyl glutathione. I've heard from one person who has used it, and it has raised the glutathione level in immune cells in the blood. Again, I think this will be a temporary effect unless the methylation cycle block is lifted. If you want to read about this, my papers are posted here:

    Best regards,

  10. donnaba

    donnaba New Member

    thanks rich!