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, Rich 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. Source Department of Food Science and Nutrition, Sultan Qaboos University, Muscat, Sultanate of Oman. Abstract BACKGROUND: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. PMID: 21121936 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.