Hi, cig and aquariusgirl.
To the best of my current understanding, all the cobalamin forms except glutathionylcobalamin can be hijacked by toxins. There are still some parts of B12 metabolism that have not been sorted out completely by the researchers in this field, but here's a synopsis of what is believed to be known at this point:
When various forms of B12 are taken orally via food or ordinary oral supplements (not sublingually, transdermally, liposomally or by injection) in a normally operating digestive system, all the forms of B12 are separated from protein by acid in the stomach, and are bound to haptocorrin. In the early part of the small intestine, the haptocorrin is broken down, and the B12 forms are bound to intrinsic factor, which is produced by the parietal cells of the stomach. In the last part of the small intestine (the terminal ileum) there are receptors for intrinsic factor, and it is drawn into the cells lining the intestine (enterocytes), together with the forms of B12 that are bound to it. The enterocytes transfer the B12 forms to transcobalamin, which is carried in the blood to the various cells of the body. The cells have receptors for transcobalamin, and they draw it into lysosomes inside the cells. In the lysosomes, the transcobalamin is broken down, and the forms of B12 are freed. They are passed from the lysosomes into the cytosol, and their beta ligands are removed. These include hydroxo-, methyl-. and adenosyl-. At this point the B12 is just cobalamin. The cobalamin is then passed either to methionine synthase in the cytosol or into the mitochondria. The fraction that is passed to methionine synthase is methylated by SAMe to become methylcobalamin and it supports the methylation cycle. The fraction that passes into the mitochondria is converted to adenosylcobalamin, and it supports methylmalonyl-CoA mutase.
It has been proposed that during its metabolism in the cytosol of the cells, B12 is normally chaperoned by proteins over its entire pathway to formation of the B12 coenzyme forms. There is evidence that glutathione is involved in this chaperoning process, by formation of glutathionylcobalamin, which protects cobalamin from reacting with toxins during its transition from the initial form that was absorbed to its final coenzyme form, either methylcobalamin or adenosylcobalamin. But the details of this process are still not totally elucidated. I have hypothesized that this need for chaperoning is the reason why depletion of glutathione leads to loss of B12 function, and thus a partial block of the methylation cycle as well as a partial block of the methylmalonate reaction, which causes methylmalonate to rise in the urine organic acid tests.
Note that all forms of B12 that are taken by the ordinary oral route are normally treated the same way. Their individual ligands are removed, and then the two coenzyme forms of B12 are produced as needed by the cells. Because of this, the intake form of B12 are all vulnerable to hijacking, if there is not enough glutathione to protect the intermediate cobalamin.
Now, what about taking high dosages of forms of B12 by the artificial routes (sublingual, transdermal, liposomal, or injection)? If the dosages are high compared to usual RDA-type B12 dosages, which are in the few micrograms range, that is, if they are up to several milligrams, 1000 times higher than RDA-type levels, then the capacity of transcobalamin to bind the B12 in the blood will be overwhelmed. The transcobalamin will be saturated, and it will carry its bound B12 to the cells in the normal way. The B12 in excess of this will be carried in the blood in an unbound state. As far as I know, the behavior of this unbound B12 has not been researched, but based on the experiences of many people, it appears that some of it is able to diffuse across cell membranes and enter cells without benefit of the transcobalamin receptors. Whatever does not enter the cells in this way is extracted from the blood by the kidneys and passes into the urine.
Again, the behavior of unbound B12 forms after they diffuse into the cytosol of the cells has not been researched. However, based on experiences reported, at least some of both methylcobalamin and adenosylcobalamin appear to be able to perform their normal coenzyme functions after entering the cells in this manner. If the dosages are high enough, they can apparently overwhelm the hijacking by toxins sufficiently so that some survives to perform their normal functions. In the case of hydroxocobalamin given by these artificial routes, some apparently enters the cells, and it must be converted to methylcobalamin and adenosylcobalamin inside the cells, even though it did not come in via the transcobalamin mechanism, because the experimental evidence is that it does support the normal coenzyme functions of B12.
If a person has normal cobalamin processing enzymes in their cells, it seems to me that after sufficient detoxication has taken place and glutathione levels have been restored, the hijacking of B12 by toxins will decrease, and the amount of B12 supplementation needed should also decrease. It may take considerable time to get the toxin load down, though, especially if the person has been ill for a long time, and the toxins have built up considerably while the detox system was dysfunctional.
On the other hand, there are people who have genetic mutations in one or more of the intracellular B12 processing enzymes. These are called inborn errors of metabolism. In these cases, the cells may not be able to utilize B12 and make its own coenzyme forms in the normal way. If this is the situation, then the person may have to continue to take high-dosage B12, either methylcobalamin or adenosylcobalamin or both, depending on the mutations present. freddd has reported that this is his situation. Based on his experience that taking glutathione or its precursors caused a major setback in his B12 function, it would seem that his inborn error of metabolism must involve a step downstream of the formation of glutathionylcobalamin. Apparently, once glutathione combines with cobalamin, his cells are not able to use it to make the coenzyme forms. I don't think this is the situation with most people who have ME/CFS. Therefore, I think that with time, most will be able to drop back on their B12 dosages. There are a small number who have reported what appears to be complete recovery, and as far as I know, they haven't continued taking high dosages of B12, but I don't really have much data on this. I would very much appreciate hearing from people about their experiences with this.
I should also note that there are people who have various other problems in B12 handling. Some have low stomach acid, so that they are not able to liberate B12 from protein in the stomach. Some have pernicious anemia, so that they don't have enough intrinsic factor, and thus can't absorb B12 from the gut. Some have had an intestinal disease such as Crohn's or celiac, or they have had part of their intestine removed surgically, so they also cannot absorb B12 well from the gut. Some have a transcobalamin deficiency, so that they can't bind B12 and transport it properly in the blood. Some may lack transcobalamin receptors on their cells, and so on.
Just for completeness, let me note that the cells apparently export extra B12 that they don't need back to the blood, bound to haptocorrin. This actually constitutes most of the B12 that is normally found in the blood at any time. This B12 is eventually imported by the liver. Some is stored in the liver, and some is excreted in the bile, passing back to the intestine, where is again available to be bound to intrinsic factor and reabsorbed. This part of the B12 metabolism has not been completely researched, but apparently it is a salvage pathway that avoids wasting B12 and provides it at times when not much is coming in from the diet.
Best regards,
Rich
take care and thanks once again.