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Cobalamin review paper - Advances in the Understanding of Cobalamin Assimilation

Discussion in 'Detox: Methylation; B12; Glutathione; Chelation' started by voner, Jul 14, 2011.

  1. voner

    voner Senior Member

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    I ran across this paper while doing some other research. It's from October 2009. hopefully it might be of some help for somebody....

    here's the website:

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2809139

    here is the title:

    Advances in the Understanding of Cobalamin Assimilation and Metabolism


    here is the Summary:

    The haematological and neurological consequences of cobalamin deficiency define the essential role of this vitamin in key metabolic reactions. The identification of cubilin-amnionless as the receptors for intestinal absorption of intrinsic factor-bound cobalamin and the plasma membrane receptor for cellular uptake of transcobalamin bound cobalamin have provided a clearer understanding of the absorption and cellular uptake of this vitamin. As the genes involved in the intracellular processing of cobalamins and genetic defects of these pathways are identified, the metabolic disposition of cobalamins and the proteins involved are being recognized. The synthesis of methylcobalamin and 5deoxyadenosylcobalamin, their utilization in conjunction with methionine synthase and methylmalonylCoA mutase, respectively, and the metabolic consequences of defects in these pathways could provide insights into the clinical presentation of cobalamin deficiency.
  2. Freddd

    Freddd Senior Member

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    Hi Voner,

    And one of these decades they might get a clue that larger amounts than the 10mcg or so that the active system can handle actually gets to the cells very rapidly by diffusion and enhances and speeds up healing. Thank you for the paper reference. It is a clarification on certain technical matters of the active absorbtion system but is totally useless in terms of the active b12 protocol and the healing it produces. At the rate of advances indicated by this paper they have another 100 years or so to go to figure out what we are applying here. They might even increase the symptoms list for b12 deficiency to include the hundreds more on the list posted here, for both active b12s, compared to the lists used for the inactive cobalamin deficiencies. It's great that they are beginning to realize that there are neurological problems caused by the lack. However, we'll all likely be long dead before they figure that out.
  3. Richard Lee

    Richard Lee

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    This paper is interesting. I read it a few months back while trying to understand how B12 is absorbed into cells by diffusion.

    I have drawn a blank trying to uncover research which examines the extent to which unbound B12 passes into cells by diffusion in vivo. Even in vitro, I am aware (thanks to Kevin Byrne) of only one paper:
    1985 Release of vitamin B12 from carrier erythrocytes in vitro.

    This 2009 paper seems to deny that meaningful diffusion into cells takes place at all:

    "Early studies had recognized that free Cbl is not internalized in cells and a serum component is required for cellular uptake of physiological concentrations of Cbl. The serum component was subsequently identified as TC.

    "Studies to define the pathway for cellular uptake of Cbl provided clear evidence of enhanced uptake of TC-bound-Cbl. This uptake involved binding of TC-Cbl to the cell surface and internalization of the TC-Cbl complex."


    I wonder if our assumption that megadoses of B12 enters cells by diffusion is correct. Might it be that it first binds to apoTC in the blood, and is then carried into cells as holoTC, while the body generates replacement-apoTC to maintain a balance?

    Another interesting fact to emerge from this paper is that "receptors are expressed to meet increased Cbl requirement during DNA synthesis and once this requirement has been met, the excess Cbl is effectively transported out of the cell and is captured by circulating apoTC for mobilization to where it is needed most."

    That implies that unbound Cbl is no stranger to the bloodstream, and should not be perceived as alien, though it might be perceived as excess to requirements if it reaches the kidneys without being intercepted by apoTC (or by apoHC).
  4. Freddd

    Freddd Senior Member

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    Hi Richard,


    I have drawn a blank trying to uncover research which examines the extent to which unbound B12 passes into cells by diffusion in vivo. Even in vitro, I am aware (thanks to Kevin Byrne) of only one paper:
    1985 Release of vitamin B12 from carrier erythrocytes in vitro.


    This 2009 paper seems to deny that meaningful diffusion into cells takes place at all:

    Yep. This is based on assumptions generated by 60 years of research on cyancbl and hydroxcbl which severely cripples the understanding of how the two active cobalamins function. Recent research shows dose proportionality (with normal absorption functioning) from 1-125 mcg at at which point the active system is saturated. Previously no dose proportionality had been detected with hycbl and cyanocbl. Composites of other research with methylcobalamin indicates that a dose proportionality exists from 1-50,000 mcg at least. Actual experience indicates that both mb12 and adb12 can start causing noticeable effects within 5 minutes of starting a sublingual tablet and increases for the entire time the sublingual remains in contact, at least before equilibrium is reached and maintained. That these two affect 200-300 more symptoms than cyanocbl and hydroxcbl indicates that they are a very different breed and they affect another 100 more quickly and completely. Until the research tells us that and why, it is basically legacy research based on inactive cobalamins and doesn't address the issues that we are faced with every day. The research questions are being asked on a theoretical basis using assumptions from other research on inactive cobalamins. GIGO.
  5. voner

    voner Senior Member

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    I took two other things (that I could understand) from the article.

    1. As Fredd noted, in order for the b12 get into the bloodstream -- it has has be absorbed into the body through the gut. Considering the intestinal issues that may ME/CFS folks have, I wonder how much cobalamin is absorbed through our guts? this is important to consider -- because it's first in line, it's not how much of the substance you ingest -- rather how much is adsorbed into the bloodstream. --

    2. Dr. Edward V. Quadros has been researching b12 and it's role in the human body for a very long time. I would love to hear his take on Rch VanKs and Fredds discussions.

    Rich or Fredd, you ever had discussions with Dr. Edward V. Quadros?
  6. Freddd

    Freddd Senior Member

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    Hi Voner,

    it has has be absorbed into the body through the gut.

    FALSE! FALSE! FALSE!

    This is one of the BIG myths. That is how b12 must be absorbed from food. Sublingual or under the lip against the gums works 10-33 times better than the gut absorbtion. As I also inject the mb12 and injection is frequently used in all sorts of b12 therapies from ineffective to effective this statement makes no sense at all.


    Rich or Fredd, you ever had discussions with Dr. Edward V. Quadros?


    No, I have not but I would be glad to.


    Considering the intestinal issues that may ME/CFS folks have, I wonder how much cobalamin is absorbed through our guts?


    Very little for a lot of people. As the gut issues may be caused or made worse by lack of methylb12 and/or methylfolate in the first place it becomes a positive feedback cycle that gets worse and worse. As stomach acid decreases with age, and as a result of mb12 deficiency, it is estimated that even if there is no other reason for hindered absorbtion that as much as 50% are becoming deficient by age 50. Most people with deficiency never find out why. Actual pernicious anemia (not anemia actually but rather IF non-functioning for any of several reasons, another semantic confusion) is rare.
  7. richvank

    richvank Senior Member

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    Hi, Voner.

    I haven't communicated with Dr. Quadros, either. Maybe I'll try that at some point. I think it should be borne in mind, though, that he's an academic, and he is reviewing the results of research that has been published in peer-reviewed journals. Quite a bit of what Freddd and I discuss here does not fit into that category, and would be considered anecdotal and thus not scientifically established. To transform it into the other category would require clinical or laboratory research which has not been done, and which would require considerable funding, the appropriate facilities, and a lot of effort and time. Hopefully some day it will be done.

    Note that Dr. Quadros writes, "The absorption of PHYSIOLOGICAL [my emphasis] concentrations of cobalamin occurs via intrinsic factor and the receptor for intrinsic factor--cobalamin, cubulin, a peripheral membrane-associated protein expressed in the distal ileum." The term "physiological" is a jargon word that means what is normally found, that is, in this case, with a normal diet and without supplementation.

    Note that he also writes, in reference to oral supplementation of cobalamin, "At doses of 1-2 milligrams, approximately 10 micrograms of the vitamin may be absorbed via nonspecific internalization in both normal subjects and in patients with malabsorption. Such high dosages of oral cobalamin are considered as effective as periodic intramuscular injections in restoring cobalamin status."

    So he does acknowledge that B12 can be absorbed from the gut without the help of intrinsic factor, if the supplemented oral dosage is high enough. Note that he calls it "nonspecific internalization." That's pretty vague, because it isn't known how it happens. Does it happen by diffusion through the cell walls of the enterocytes, or does it happen by diffusion through the gap junctions between the enterocytes, or what? Nobody knows. If it happens by diffusion through the cell walls, then that would suggest that it also might later diffuse from the blood through the walls of other cells in the body, which is apparently what is happening with Freddd's treatment.

    Note that in discussing cellular uptake of cobalamin he writes, "Early studies had recognized that free cobalamin is not internalized in cells and a serum component [transcobalamin, my insertion] is required for uptake of PHYSIOLOGICAL concentrations of cobalamin." Note again that he is referring to physiogical concentrations. When cobalamin is given sublingually or by injection, the concentrations are much higher than physiological concentrations. So I don't think Dr. Quadros is ruling out diffusive uptake by cells when the concentration of cobalamin in the blood serum is considerably higher then physiological levels.

    I did write to Prof. Ruma Banerjee, another researcher in this area, asking what she thought about the diffusion possibility, but I haven't received an answer. I don't think anybody has studied it in a controlled way. Most scientists don't like to speculate to people they don't know, without evidence.
    be
    Perhaps what we could do is to try to get the researchers interested in studying cellular uptake of cobalamin when there are super-physiological concentrations in the blood serum. This would not applicable to normal physiology, but it would certainly be applicable to treatment of disorders. NIH funds study of normal physiology. Treatment research is funded mostly by the drug companies, but cobalamin can't be patented, so there isn't a financial incentive for them to research it.

    Best regards,

    Rich
  8. biophile

    biophile Places I'd rather be.

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    Oral vs sublingual, and high doses of B12

    I was going to post this on another thread (http://forums.phoenixrising.me/showthread.php?188-B-12-The-Hidden-Story) but then I noticed this thread and the same issue I was going to comment on was raised here.

    I tried finding more information on PubMed but the research is sparse.

    Sharabi et al 2003 states that there is no difference between taking B12 orally or sublingually, which studied serum cobalamin concentrations after administering cyano-B12 (http://www.ncbi.nlm.nih.gov/pubmed/14616423). AFAIK it doesn't specify how long the dosage was held under the tongue.

    In another study people were given 1000mcg methylcobalamin, 400mcg folic acid, 5 mg B6 (as pyridoxine hydrochloride); the route (oral vs sublingual) made no difference in total homocysteine concentrations. (http://www.ncbi.nlm.nih.gov/pubmed/17109579)

    I'm not willing to dismiss personal experiences though, especially if it is unclear how long the sublingual doses in these studies were kept under the tongue, or how relevant blood levels of B12 and homocysteine are. I must admit that the prospect of holding tablets under the tongue for 45 minutes a day is not exciting.

    The case for ultra high doses of (oral) B12 to correct deficiencies is good, for example:

    According to this review the proportion of absorbed B12 declines exponentially as the dosage increases: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2532799/table/T1/#TF1-4

    Another study using cyano-B12 on older people concludes that "The lowest dose of oral cyanocobalamin required to normalize mild vitamin B(12) deficiency is more than 200 times greater than the recommended dietary allowance..." (http://www.ncbi.nlm.nih.gov/pubmed/15911731)

    Also in a review, "These studies suggest that at least 1000 microg/day of oral cyanocobalmin are needed for pernicious anemia and a mean daily dose of 250 microg for food-cobalamin malabsorption." (http://www.ncbi.nlm.nih.gov/pubmed/19032377)

    Currently as part of the "methylation protocol" I am sticking to taking both methyl-B12 (mornings with folinic acid) and hydroxy-B12 (evenings with FolaPro) and intend on increasing the dosage and/or adding adenosyl-B12.
  9. Freddd

    Freddd Senior Member

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    Hi Biophile,

    Sharabi et al 2003 states that there is no difference between taking B12 orally or sublingually, which studied serum cobalamin concentrations after administering cyano-B12 (http://www.ncbi.nlm.nih.gov/pubmed/14616423). AFAIK it doesn't specify how long the dosage was held under the tongue.

    According to this review the proportion of absorbed B12 declines exponentially as the dosage increases:

    Oral cobalamins, of whatever form, are absorbed at near 100% for the first 10mcg via IF, with the absorbtion rate falling off rapidly to 1% or so, which is the reason why an oral 1000mcg dose of cyanocbl (I refuse to call this largely inactive accidental vitamer "B12" despite it's oficial name) maintains the serum level at least as well as monthly 1000mcg injections of cyanocbl. A study of sublingual cyanocbl absorption without taking tissue contact time into account is fatally flawed. Further the pharmacodynamics of the various cobalamins is reasonably well studied. Cyanocbl is the fastest excreted by the kidneys, but that is only slightly faster than the others. In general, after injection, cobalamin is excreted by the kidneys at a serum halflife of 20-50 minutes. After about 4 hours that starts coming down and by 12 hours it is down to a 4 hour serum halflife. From 12-48 hours post-injection various studies place the serum halflife in the 12-12.9 hours average. From 2 days to 14 days the serum halflife of a single injection continues falling off reaching it's equilibrium value of 10-200 days or so depending upon the person. After 24 hours these various studies show that 98-99% of the injected cobalamin has been excreted. A 10 mcg absorbed dose has the ability to raise the serum level by 2000pg/ml minus whatever is taken in by the tissues. A sublingual chewed or slurped down quickly absorbs about the same amount as a swallowed oral dose.

    I did a study of sublingual methylb12 and adenosylb12, separately and together. The methylb12 study was more extensive. I did a series of injections, originally 1-25mg recently extended to 60mg in a single dose and 180mg daily, comparing it to Jarrow 5mg methylb12 in doses of 10mg to 50mg (originally) and extended to 100mg. The oral and injection series each contains hundreds of separate doses. The amount absorbed can be easily seen as it colors the urine after a certain amount. Cobalamin CAN'T get into the urine without being absorbed into the blood first. The amount in the urine can be compared easily via colorimetry. The method I used was subtractive color print filters to make the urine a neutral gray. As cobalamin is almost pure deep magenta ragther than red, the method works very easily. The filters are graded in steps of "05", which is a "just noticable difference, 1/3 stop". So the more magenta in the urine the more cyan and yellow needed to totally neutralize it. In me, the first visiblity in the first series without Metafolin, is at 2.5mg injected and about 8mg sublingual with some variability. When all was said and done, the absorption rate of these sublinguals ranged from min = 10% to max = 33% with 2 standard deviations encompassing 15-25%. The minimum values were achieved at 45 minutes and the maximum values at 120 minutes. With Metafolin first visibility is at 4.4mg injected. Metafolin increased the amounts needed sublingually and injected proportionately.

    With glutathione precursors 30mg mb12 injected daily urine is colored as much as with 120mg injected daily without glutathione and with Metafolin while not in folate deficiency.

    In all cases most of the cobalamin is exceted in the first several hours as one would expect from the pharmacodynamic studies.

    Additionally a smaller series was done with Enzymatic Therapy 1mg tablets. Similar results were obtained with Country Life Dibencozid (adb12) 3mg. 50-51 mg sublingual/buccal (50x1mg tablets is a whole mouth-full). Combinations were also very similar.

    As dose proportionate neurological effectiveness of mb12 has been documented in a number of studies over the range of 120-50,000 mcg, and cyanocbl has almost no effectiveness neurologically, and maximum effect on Hcy is reached with perhaps 10mcg, the study quoted couldn't posible show anything other than what it did.

    If they had studied cerebral spinal fluid HCY levels in MS patients the results would have been very different if done with much larger doses of mb12 needed to penetrate CSF as shown in Japanese studies. Sublingual or oral doses of cyanocbl would have the same effect on the CSF Hcy also, NONE.

    As both of these show, if you ask carefully constructed limited questions in research you get limited answers. As all of these research questions asked were asked of the largely inactive vitamer cyanocobalamin the answers were exactly as expected based on decades of similarly constructed research.

    The application of the these answers on cyanocbl have only limited bearing on methylb12 and adenosylb12 and would also be somewhat different with hycbl. Cyanocbl is the least active least effective cobalamin that has any effectiveness at all. It is the worst possible therapy that isn't totally inactive.


    Currently as part of the "methylation protocol" I am sticking to taking both methyl-B12 (mornings with folinic acid) and hydroxy-B12 (evenings with FolaPro) and intend on increasing the dosage and/or adding adenosyl-B12.

    Good. The next thing you might investigate in yourself is whether folinic acid causes paradoxical folate deficiency in you or not. I must stress that how effective these can be is limited by lack of other cofactors. Watch out for induced low potassium as methylation starts up. It is often mistakenly called "detox" but can be relieved in 30-60 minutes with a 500mg dose of potassium.
  10. voner

    voner Senior Member

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    I have a personal question for you guys -- I've had a couple periods of time were I receive some form of "Myers cocktails" -- intravenous infusions that had a ton of vitamin B12 (what form -- I don't know it was a while ago years ago), but I never had any response to these miners cocktails.

    I guess the obvious answer would be -- wrong form of vitamin B12?
  11. drex13

    drex13 Senior Member

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    Freddd,
    A quick question regarding potassium supplementation. When you refer to a 500 mg dose of potassium, are you referring to a (for example) single 500 mg potasssium gluconate tablet that provides 99 mg of potassium, or are you talking about taking 5 of these tablets at a time (2500 mg potassium gluconate, providing roughly 500 mg of potassium) ? Thanks, Drex
  12. biophile

    biophile Places I'd rather be.

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    Freddd, your experiments are impressive and you seem to be in a unique situation to be able to conduct them. As for the issue of whether folinic acid is good or bad for me ...

    I started out several weeks ago with just 200mcg FolaPro and 250-500mcg hydroxy-B12 (evenings was best to manage side effects). The startup seemed to be less than last year when I tried it for several weeks and gave up. When I adjusted recently to the response I sometimes added 200mcg folinic acid and 1000mcg methyl-B12 (drops from holisticheal.com) but not at the same time, in order to discern effects.

    Experimentation suggested to me that the folinic acid is better to take in the morning, at a different time to FolaPro, to reduce overall impact. Also it seems better for me to take methyl-B12 in the morning just in case it has (suspected) stimulant effects that affect my sleep, also at first I noticed possible grogginess about 12 hours afterwards which better coincides with sleep time when taken in the morning. I suspect the methyl-B12 is helping.

    Your experiences with folinic acid concerned me. At first the folinic acid seemed to cause a similar and additive response as FolaPro but less harsh. I have adjusted to those effects as well, if anything the folinic acid may now be helping further. I considered the possibility that the folinic acid is "helping" me by blocking the adverse effects of FolaPro but somehow that seems unlikely for me. Whatever I'm doing at present seems better than before, as far as I can tell the folinic acid isn't having a deleterious effect. What is the best way to tell if it is?

    From the limited research I've done and also the reading I have done on this forum about richvank's approach and your approach (and Dr Nathan's Q&A http://www.prohealth.com/library/showarticle.cfm?libid=16338), combined with the preliminary experimentation I have done, I think I will remain with both forms of folates for now since they seem OK.

    I haven't ordered the (Jarrow) methyl-B12 and (Source Naturals) adenosyl-B12 lozenges yet. Right now I'm working on increasing to 2000mcg+ methyl-B12 and maybe to 1000mcg hydroxy-B12 per day, and possibly increasing the FolaPro to 400mcg if tolerated, last year this wasn't achievable but I'm encouraged by this years improved tolerance to it.

    Still working on the cofactors, that has been more difficult.
  13. Valentijn

    Valentijn Activity Level: 3

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    There's a list of the ingredients at http://en.wikipedia.org/wiki/Myers'_cocktail , though it's certainly possible it started off with a different form of B12. The problem might also be with the B Complex component, which almost always contains folic acid. I believe the prevailing theory here is that folic acid competes with folate and usually wins, which is problematic if you can't convert folic acid into folate properly. Plus the Myers Cocktail looks like it lacks quite a few things that help with methylations and such. So maybe it helped for people whose primary problem was B12 deficiency, until they ran into a secondary deficiency or something.
  14. voner

    voner Senior Member

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    Valentijn:

    thanks. That might explain it.

    Now what if you got a Myers cocktail type intravenous line-- with the right ingredients in it? When I used to get those -- I would sit in a chair for like an hour or even 2 and let it drip in. I do that a couple times a week. It was absolutely no help -- but maybe not the right ingredients. That way you would get the substances into your bloodstream for sure and not have to depend on your body to properly absorb the ingredients.

    thanks again.
  15. Freddd

    Freddd Senior Member

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    Hi Drex,

    I was unclear. 5x99 which is actually 495mg of potasssium.
  16. Freddd

    Freddd Senior Member

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    Some versions of the Myers cocktail contaqin glutathione or precursurs and that can prevent mb12 and methylfolate from working or the methyb12 could have been exposed to enough light to break it down to hydroxcbl which won't have the same effect. Was the bag/bottle very dark or opaque along with the tubes? If not it coukld degrade on the spot.

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