How Does Vitamin C as Ascorbic Acid Enter Cells?

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Re: How Does Vitamin C as Ascorbic Acid Enter Cells?

Post Number:#16  Post by ofonorow » Tue Jan 29, 2013 6:16 am

Thank you Steve, for your research and interest in this topic. I started this topic because common sense dictates that vitamin C enters cells in its reduced (non oxidized) form and thus becomes the "rate unlimited" free-radical antioxidant Cathcart wrote about. Yet, from the literature we are led to believe that the GLUT transporters are in some way dominant.

Again, what I was able to make out from johnwen's link to the liver cell SDVC transporter paper - no mention of GLUT - was that ascorbic acid (with NA+ present) enters cells (depending on pH, temperature, NA+, etc.)


Steve Brown wrote:I've done further reading on this topic, and it appears that both GLUT and SVCT are involved in the transport of vitamin C into various cells. GLUT transports dehydroascorbic acid (DHA), and SVCT transports ascorbate. However, only DHA can be transported into the mitochondria within cells, and only DHA can enter the brain through the blood/brain barrier. DHA competes with glucose for transport into cells, and so the amount of DHA that is absorbed depends on the concentration of glucose in the blood. This may cause a person who consumes so much sugar that he or she has too much glucose in the blood to have cellular deficiency of vitamin C, at least in terms of supplying the mitochondria with vitamin C.


As you say DHA, although short-lived, can be dangerous, so having GLUT transporters remove it from the blood makes biological and evolutionary sense.

I am not certain about the mitochronria - (Russell Jaffe in his lectures mentions that Alpha Lipoic Acid is the "natural" antioxidant in the mitochondria, and that vitamin E is the antioxidant generally protecting the cellular membrane, etc.) but again, it makes no common sense that vitamin C only enters the brain as the "dangerous" DHA. I (think I) know from Sherry Lewin, that DHA is more permeable to lipid membranes, but I would be a Quarter that there are SDVC Transporters, a slew of them, at the blood-brain barrier.
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Re: How Does Vitamin C as Ascorbic Acid Enter Cells?

Post Number:#17  Post by Steve Brown » Tue Jan 29, 2013 3:14 pm

ofonorow wrote:
I am not certain about the mitochronria - (Russell Jaffe in his lectures mentions that Alpha Lipoic Acid is the "natural" antioxidant in the mitochondria, and that vitamin E is the antioxidant generally protecting the cellular membrane, etc.) but again, it makes no common sense that vitamin C only enters the brain as the "dangerous" DHA. I (think I) know from Sherry Lewin, that DHA is more permeable to lipid membranes, but I would be a Quarter that there are SDVC Transporters, a slew of them, at the blood-brain barrier.


From the Wikipedia article on dehydroascorbic acid:

"Although there exists a sodium-dependent transporter for vitamin C, it is mainly present in specialized cells, whereas the glucose transporters, most notably GLUT1, transport Vitamin C (in its oxidized form, DHA) in most cells, where recycling back to ascorbate generates the necessary enzyme cofactor and intracellular antioxidant.

"Transport to mitochondria

"Vitamin C accumulates in mitochondria, where most of the free radicals are produced, by entering as DHA through the glucose transporters, GLUT1. Ascorbic acid protects the mitochondrial genome and membrane.

"Transport to the brain

"Vitamin C does not pass from the blood stream into the brain, although the brain is one of the organs which has the greatest concentration of vitamin C. Instead, DHA is transported through the blood-brain barrier via GLUT1 transporters, and then converted back to ascorbate."

http://en.wikipedia.org/wiki/Dehydroascorbic_acid

From an article in the Journal of Clinical Investigation:

"Ascorbic acid was not able to cross the blood-brain barrier in our studies. In contrast, the oxidized form of vitamin C, dehydroascorbic acid (oxidized ascorbic acid), readily entered the brain and was retained in the brain tissue in the form of ascorbic acid."

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC508490/

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Re: How Does Vitamin C as Ascorbic Acid Enter Cells?

Post Number:#18  Post by ofonorow » Sun Feb 03, 2013 2:44 pm

Steve, if you are not a chemist, you at least play one at this forum.

These statements to me - a non chemist - violate common sense, the reason I started this topic.

Before examining each statement separately, how do you think it works at the macro level?

Is DHA an oxidant or antioxidant?

If the DHA is also an antioxidant, just less potent than AA, that would clear things up some, and these claims do not violate common sense. And this may be. (I notice in Sherry Lewis's diagrams there is another break down product called the ascorbate free radical.)

At a high level - the antioxidant vitamin C should readily enter cells. The ability to mop up DHA in the blood, using GLUT transporters, and recyling makes sense.

The statements you quoted do not make sense unless there is something basic missing, such that DHA
is not a pro oxidant, but another antioxidant?!

Regarding SVCT being more specialized - if true, why wasn't GLUT even mentioned in that study johnwen cited of how ascorbate enters liver cells?

Common sense tells us that ascorbic acid has a means of entry into all cells - either as the ascorbate ion, ascorbic acid, or sodium ascorbate.


"Vitamin C does not pass from the blood stream into the brain, although the brain is one of the organs which has the greatest concentration of vitamin C. Instead, DHA is transported through the blood-brain barrier via GLUT1 transporters, and then converted back to ascorbate."


Okay, Steve or someone, can you describe how this magic recycling occurs? (Actually didn't we have this discussion already, and I believe that johnwen came up with a university pictorial diagram showing how vitamin C enters the brains via SVCT transporters.
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Re: How Does Vitamin C as Ascorbic Acid Enter Cells?

Post Number:#19  Post by ofonorow » Sun Feb 03, 2013 2:51 pm

Diagram http://www.biocarta.com/pathfiles/m_vitcbpathway.asp

from our previous discussion

Svct1 and Svct2 are ascorbate transporters for vitamin C import into tissues and into cells. Both of these transporters specifically transport reduced L-ascorbic acid against a concentration gradient using the intracellular sodium gradient to drive ascorbate transport. Svct1 is expressed in epithelial cells in the intestine, upregulated in cellular models for intestinal epithelium and appears to be responsible for the import of dietary vitamin C from the intestinal lumen. The vitamin C imported from the intestine is present in plasma at approximately 50 uM, almost exclusively in the reduced form, and is transported to tissues to play a variety of roles. Svct2 imports reduced ascorbate from the plasma into very active tissues like the brain.


http://www.vitamincfoundation.org/forum/viewtopic.php?f=3&t=9820&p=29508&hilit=GLUT+and+Brain#p29508
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Re: How Does Vitamin C as Ascorbic Acid Enter Cells?

Post Number:#20  Post by skyorbit » Sun Feb 03, 2013 3:54 pm

ofonorow wrote:Okay, Steve or someone, can you describe how this magic recycling occurs?


The cells in the brain manufacture GSH, ALA, and other anti-oxidants that donate electrons to the C and recharge it.

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Re: How Does Vitamin C as Ascorbic Acid Enter Cells?

Post Number:#21  Post by Steve Brown » Thu Feb 07, 2013 12:36 pm

Tracy in the above post is correct.

Owen, I'm not a chemist but I have studied chemistry and understand the basics of molecular bonds, acids, bases, salts, oxidation, reduction, and stoichiometry. I'm interested in the biochemistry of vitamin C and that is why I engage in discussions on this forum and research the topic, seeking reliable sources of information on the internet. Specifically with regard to vitamin C transporters, it is my understanding that the sodium-dependent transporters predominate in some cells, and the glucose transporters predominate in others. The intestine is one place where the SVCT transporters have a prominent role in transporting ascorbate into the bloodstream. Red blood cells, however, do not have SVCT transporters; they have GLUT transporters which move DHA into the cells where it is reduced back to ascorbate. Here is a link to an article that lists the twelve different transporters on the outer membrane of red blood cells, which does not include SVCT transporters: http://en.wikipedia.org/wiki/Red_blood_cell

Following is a link to an article in Science Daily about research into the mechanisms of vitamin C transport into and retention by the brain. Quote: "The researchers found that ascorbic acid was not able to cross the blood brain barrier, while dehydroascorbic acid readily entered the brain and was retained in the tissue as ascorbic acid."

http://www.sciencedaily.com/releases/19 ... 133607.htm

Regarding your question about whether DHA is an oxidant or an antioxidant, it is neither. It is an oxidized but fairly stable or unreactive form of vitamin C. Quoting from the article linked to below: "Dehydroascorbic acid (DHA) is an oxidized form of ascorbic acid. It is actively imported into the endoplasmic reticulum of cells via glucose transporters. It is trapped therein by reduction back to ascorbate by glutathione and other thiols."

http://en.wikipedia.org/wiki/Dehydroascorbic_acid

Also quoted from the above article:

"Transport to mitochondria

"Vitamin C accumulates in mitochondria, where most of the free radicals are produced, by entering as DHA through the glucose transporters, GLUT1. Ascorbic acid protects the mitochondrial genome and membrane.

"Transport to the brain

"Vitamin C does not pass from the blood stream into the brain, although the brain is one of the organs which has the greatest concentration of vitamin C. Instead, DHA is transported through the blood-brain barrier via GLUT1 transporters, and then converted back to ascorbate"

DHA is doubly-oxidized, but the singly-oxidized form, known as semidehydroascorbic acid, is a free radical, called the ascorbyl radical. It can be further oxidized to DHA by an antioxidant such as thioredoxin reductase, an enzyme that contains selenium and sulfur.

http://www.jbc.org/content/273/36/23039.full
Last edited by Steve Brown on Thu Feb 07, 2013 4:19 pm, edited 2 times in total.

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Re: How Does Vitamin C as Ascorbic Acid Enter Cells?

Post Number:#22  Post by majkinetor » Thu Feb 07, 2013 1:45 pm

Its well known nowdays that C enters the brain via choroid plexus using SVCT2 transporters and via GLUT.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2649700/

See 2.1 Routes of ascorbate entry into the CNS

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Re: How Does Vitamin C as Ascorbic Acid Enter Cells?

Post Number:#23  Post by Steve Brown » Thu Feb 07, 2013 4:14 pm

majkinetor wrote:Its well known nowdays that C enters the brain via choroid plexus using SVCT2 transporters and via GLUT.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2649700/

See 2.1 Routes of ascorbate entry into the CNS


Thank you for posting the link to that article, which is from an authoritative source, covers the topic in depth, and provides information that is more up to date than information I have obtained from other sources. Truth is more important to me than being right. While the blood-brain barrier remains a barrier to the direct flow of ascorbate into the brain, ascorbate detours into the brain via the cerebrospinal fluid. The sodium-dependent transporters predominate for most cells, except for the red blood cells, which appear to rely on the GLUT transporters for the uptake of vitamin C. What I found interesting is the following excerpt, which suggests that cellular uptake by GLUT transporters becomes important in conditions of high oxidative stress, such as in the case of disease.

"Nonetheless, DHA uptake and reduction could well preserve intracellular ascorbate over short time periods in areas of high oxidant stress, where significant amounts of extracellular ascorbate are oxidized."
Last edited by Steve Brown on Thu Feb 07, 2013 4:35 pm, edited 2 times in total.

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Re: How Does Vitamin C as Ascorbic Acid Enter Cells?

Post Number:#24  Post by randian » Thu Feb 07, 2013 4:32 pm

Steve Brown wrote:The sodium-dependent transporters do appear to predominate in most cells, including those of the nervous system and brain, the major exception being the red blood cells, which appear to rely on the GLUT transporters for the uptake of vitamin C.

Which suggests that, in the normal case, one needn't worry about glucose blocking C uptake in your body. I can see why we see so many cell culture studies showing "extra C does no good". They're testing blood cells which are easy and relatively non-invasive to acquire (laziness), but which have a different uptake mechanism compared to, say, your heart where extra C is really worthwhile.
Steve Brown wrote:What I found interesting is the following excerpt, which suggests that cellular uptake by GLUT transporters becomes important in conditions of high oxidative stress, such as in the case of disease.

The excerpt quoted doesn't mention GLUT. Even so, it would not surprise me that GLUT was an auxiliary mechanism for times when extra C must be absorbed.

In animals that produce their own C, one must ask what their extra C production during sickness is good for if they're being rate limited (aka not enough transport capacity) by sodium transporters.

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Re: How Does Vitamin C as Ascorbic Acid Enter Cells?

Post Number:#25  Post by majkinetor » Fri Feb 08, 2013 2:12 pm

The sodium-dependent transporters predominate for most cells, except for the red blood cells, which appear to rely on the GLUT transporters for the uptake of vitamin C.

GLUT transporters can shift priority from glucose to DHAA. The receptor has a "switch". So competition might not take effect.
http://www.isom.eu/pdf/0803Montel-Hagen ... ydroAA.pdf
(if true, this actually makes good case against the need for megadosage)

What I found interesting is the following excerpt, which suggests that cellular uptake by GLUT transporters becomes important in conditions of high oxidative stress, such as in the case of disease.

It does, but that is only for pathogenic cases. IN such situation glucose levels are also higher so it competes more (since cortisol is secrted). But, perhaps all GLUT receptors can switch priority (which is suggested in paper about the switch)

In such cases other adaptation happen. For isntances in mices, during storke, BBB starts to express SVCT2.
http://www.plosone.org/article/info:doi ... ne.0017139

In animals that produce their own C, one must ask what their extra C production during sickness is good for if they're being rate limited (aka not enough transport capacity) by sodium transporters.

Because during stress SCVT expression may be also modulated, and there is more oxidative stress, more DHA and thus more GLUT transport.

But, I didn't find yet good reference for animal C production. All stories are returning to Paulings estimations. ITs interesting that he seemed to compare it for humangs using body weight, while that is not how it should be done:
http://suppversity.blogspot.com/2011/06 ... valen.html

Naturally, I became skeptical of claim, especially as it is clear disadvantage during femine (unless production is downregulated, which might be true).

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Re: How Does Vitamin C as Ascorbic Acid Enter Cells?

Post Number:#26  Post by ofonorow » Wed Apr 17, 2013 10:53 am

Can we summarize this discussion so far?

Ascorbic acid can enter the brain, using SVCT transporters, possibly bypassing the blood stream. (According
to Pauling the brain tightly controls the amount of vitamin C.)
Linus Pauling, Chapter 20 - The Brain" HTLLAFB wrote:In persons suffering from scurvy the concentration of vitamin C in brain is kept high even when there is almost complete depletion in the blood and other tissues.


This discussion seems to conclude that, GLUT transporters are a secondary, not a primary mechanism for transporting ascorbate through cell membranes into (and out of) cells.

And GLUT transports DHA, which, which, in theory, would be in greater supply in the blood the more stress there is.

Linus Pauling pg 89 HTLLAFB wrote:The ways in which ascorbic acid functions in the human body relates first to the fact that it engages in both sides of the universal oxidation-reduction reaction that subtracts or adds hydrogen atoms to a molecule. It is readily oxidized to dehydroaxcorbic acid by the surrender, to oxidizing agents, of the two hydrogen atoms...[diagram]

This action is readily reversible, for the dehydroascorbic acid acts as a strong oxidizing agent, and by pickup up two hydrogen atoms, is reduced to ascorbic acid. It is likely that the reducing power of ascorbic acid and the oxidizing power of dehydroascorbic acid are responsible for some of the physiological properties of the substance.


I am satisfied that vitamin C, ascorbate, the reduced form, is what generally enters cells under normal conditions.

DHA can also be accepted, by GLUT transporters. But must be reduced within the cell.

It does raise the issue of the validity of Dr. Ely's Glucose-Ascorbate antagonism theory, but as pointed out here, DHA/GLUT starts to play a role the more stress the organism is under.
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Re: How Does Vitamin C as Ascorbic Acid Enter Cells?

Post Number:#27  Post by majkinetor » Wed Apr 17, 2013 12:44 pm

Can we summarize this discussion so far?

No we can't because it is overly complex. Any mechanism is context and tissue dependent. GLUT has more then 10 isoforms and SVCT has 2.
Down/up regulation happens in certain circumstances.
There is also a switch which shifts priority.
The insulin plays a role.
The genes play the role - The Haptoglobin and SVCT expression variations which are common things in humans play a role.
Age play a role.
Bacteria may play a role.
Even diet.

So no, we can't summarize it because its too dynamic. Any summarization will be overly simplistic IMO.

Currently nobody could tell for sure what mechanism is dominant, if any (and in what phase of life). Given the importance of AA, I would suspect that redundancy is strong.

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Re: How Does Vitamin C as Ascorbic Acid Enter Cells?

Post Number:#28  Post by ofonorow » Wed Apr 17, 2013 2:50 pm

All may be important points. The reason for starting this topic is to understand how reduced ascorbate either enters or is formed inside cells.

It does not make sense the GLUT/DHA is the dominant way vitamin C is transported. Just common sense, but not well understood. I think the discussion has clarified that GLUT/DHA is a secondary mechanism, because DHA, having a short half-life, would only be present in larger quantities during stress.

If you disagree, then what is the method for reducing oxidized DHA back into AA within the cell?
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Re: How Does Vitamin C as Ascorbic Acid Enter Cells?

Post Number:#29  Post by majkinetor » Mon May 06, 2013 12:59 pm

If you disagree, then what is the method for reducing oxidized DHA back into AA within the cell?

One well known way is GSH.
http://www.sciencedirect.com/science/ar ... 1X79911823

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Re: How Does Vitamin C as Ascorbic Acid Enter Cells?

Post Number:#30  Post by ofonorow » Tue May 21, 2013 7:55 am

Which oxidizes GSH. Nothing is for free, and again the only way that makes common sense - for vitamin C to be a "nonrate limited free radical scavenger" - is for it to enter cells mostly as ascorbate (not DHA).
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