Tuesday, June 19, 2012

Proposed relationship between Lapp-Cheney B12 treatment and methylation treatme

Proposed relationship between Lapp-Cheney B12 treatment and methylation treatment
I think I now understand better why Drs. Lapp and Cheneyfound in the 1990s that a high dosage of injected vitamin B12 (they initiallyused cyanocobalamin) gave their ME/CFSpatients an increase in energy, stamina, or well-being within 12 to 24 hours,which lasted for two to three days, and why the dosage had to be so highcompared to the RDA for B12 (2,000 to 2,500micrograms per injection, compared to 2.4 micrograms per day) (as reported in the CFIDS Chronicle in 1993 and 1999). I also think I now understand better how thisfits in with the methylation-type treatments, which can bring greaterimprovement on a more permanent basis.

Here's my suggested explanation:

It is known that normally after vitamin B12 is absorbed bythe gut, it is transported in the blood to the body's cells, bound to thecarrier transcobalamin. After enteringthe cells, the B12 normally passes through an intracellular processing pathway,which produces the appropriate amounts of the two active coenzyme forms of B12needed by the cells, i.e. adenosylcobalamin and methylcobalamin.

Adenosylcobalamin acts as a coenzyme in the mitochondrialmethylmalonate pathway, which feeds certain substances into the Krebs cycle tobe used as fuel for making ATP. Thesesubstances are isoleucine, valine, threonine, methionine, the side-chain ofcholesterol, and odd-chain fatty acids.

Methylcobalamin acts in the cytosol as a coenzyme for themethionine synthase reaction, which links the methylation cycle with the folatemetabolism and also helps to govern the flow into the transsulfuration pathway,which feeds the synthesis of glutathione, among other reactions.

One of the key parts of the intracellular processing pathwayfor vitamin B12 is called the CblC complementation group. This group normally binds cobalamin in orderto carry on its processing. The strengthof this binding, called the affinity, depends strongly on the presence ofglutathione. A recent study by Jeong andKim (2011, PMID: 21821010) using bovine CblCand cyanocobalamin, found that glutathione, which is normally present in thecells, raised this affinity by a factor of over one hundred.

In ME/CFS, we have foundthat glutathione becomes depleted. Thatbeing the case, we can expect the affinity of CblC for cobalamin to dropconsiderably. The effect of this wouldbe to lower the rate of production of both adenosylcobalamin andmethylcobalamin. The effect of lowering adenosylcobalaminis to decrease the fuel supply to the Krebs cycle and hence to lower the rateof production of ATP. The effect oflowering methylcobalamin is to partially block the methionine synthasereaction, lowering the methylation capacity, and draining the methylation cycleand disrupting the sulfur metabolism in general. The methyl trap mechanism then continues toconvert other forms of folate into methylfolate, and this is partly catabolizedby reaction with peroxynitrite which forms as a result of the glutathionedepletion. The folates thus becomedepleted, and a chronic vicious circle mechanism is set up.

Now, consider what happens when a high dosage of B12 isinjected, as in the treatment discovered by Lapp and Cheney. When the dosage is high enough, the lowaffinity of the CblC complementation group for cobalamin is overcome, so thatthe rates of production of adenosylcobalamin and methylcobalamin are able tocome up, perhaps even to normal levels. I suggest that this affinity problem is the reason for the need for sucha high dosage of B12 to obtain a therapeutic effect.

The added adenosylcobalamin would support the methylmalonatepathway, and more fuel would be supplied to the Krebs cycle, which would raisethe rate of production of ATP. I suggestthat this is what causes ME/CFS patients toexperience a boost in energy, stamina or well-being on the high-dose injectedB12 treatment. This is particularlysignificant in ME/CFS, because carbohydrateand fat metabolism is hindered due to the effect of glutathione depletion onthe aconitase reaction, early in the Krebs cycle. Note also that deficiencies in some of theB-complex vitamins can interfere with obtaining this benefit, because they arealso needed by the methylmalonate pathway.

However, I suggest that even though methylcobalaminproduction would also rise, the partial block of the methionine synthasereaction would remain if B12 alone is given, and this is the reason for thelimited benefit of that treatment. The reason why B12 treatment alone will notcorrect the partial block in methionine synthase is that there is insufficient methylfolateavailable to feed this reaction. Thereason for that, as Prof. Martin Pall has pointed out, is that the level ofmethylfolate has been lowered by reaction with peroxynitrite. Peroxynitrite has risen because of the stateof oxidative stress that ensues when glutathione is depleted.

If methylfolate is added in addition to adding high-dosageB12, the partial block of methionine synthase can be lifted, which can thenbreak the vicious circle mechanism that holds glutathione down. Over time, as glutathione rises, the affinityof CblC for cobalamin will also rise, and supplementation of high-dosage B12will no longer be necessary. Likewise,peroxynitrite will drop as glutathione is restored, so that supplementation of methylfolatewill no longer be necessary, either.

Rich Van Konynenburg, Ph.D.

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