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:#31  Post by majkinetor » Tue May 21, 2013 11:15 am

Which oxidizes GSH

2 molecules of oxidized GSH become into GSH again.

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

Post Number:#32  Post by ofonorow » Tue May 21, 2013 1:12 pm

And where to the electrons come from?

According to Wiki - glutathione (and we know ascorbate can switch) between the reduced and oxidized state.

If ascorbate becomes "oxidized" by donating one of its electrons. It needs an electron back, presumably from another antioxidant?

How could two oxidized GSH molecules turn into a reduced GSH?

The only thing that seems to make sense is that GSH gets its electrons from ascorbate, which wiki says is present in the tissues at at a 60 to 4 concentration (AA to GSH)

Off to read Cathcarts "rate limited antioxidant paper"..http://www.vitamincfoundation.org/www.orthomed.com/nonrate.htm
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Re: How Does Vitamin C as Ascorbic Acid Enter Cells?

Post Number:#33  Post by ofonorow » Tue May 21, 2013 1:25 pm

http://www.vitamincfoundation.org/www.orthomed.com/nonrate.htm
EXAMPLE OF A RATE-LIMITED, ANTIOXIDANT FREE RADICAL SCAVENGING PATHWAY

In general free radical scavenging occurs through complex metabolic pathways involving many steps which are rate-limited. Deficiencies of nutrients, vitamins and minerals, which make up the enzymes and coenzymes of these systems can slow down or halt certain pathways.

It is apposite to describe one of these rate-limited, free radical scavenging mechanisms, to give the impression of its complexity and why it is rate-limited. The example chosen involves the glutathione pathway which is possibly one of the most important pathways.

When, for example, a superoxide radical must be destroyed, superoxide dismutase can catalyze its conversion to O2 and H2O2 (11). Ascorbate, nonenzamatically, also converts superoxide to H202 but is oxidized in the process to the ascorbate free radical and dehydroascorbate. The ascorbate free radical and the dehydroascorbate are reduced back to ascorbate either by NADH (catalyzed by semidehydroascorbate reductase and forming NAD) or reduced glutathione (GSH) (catalyzed by dehydroascorbate reductase and forming oxidized glutathione (GSSG)) (12). Some of the peroxide can be converted to oxygen and water by catalase but most will be destroyed by a glutathione-requiring enzyme system. GSH (catalyzed by glutathione peroxidase) reduces the peroxide to water but in the process is oxidized to GSSG. The resulting GSSG is reduced by NAD(P)H (catalyzed by glutathione reductase). The resulting NAD is reduced back to NADH by way of the Krebs cycle or resulting NADP is reduced back to NADPH by the hexose monophosphate (HMP) pathway. It is thought that commonly the rate-limiting step in the last series of reactions is that catalyzed by glutathione peroxidase and its cofactor selenium, but other substances which could limit all this are the vitamin E, vitamin C, vitamin B2, vitamin B3, cysteine, etc. Note: the ascorbate used in this example is as in the vitamin C sense; the small amount available is oxidized to dehydroascorbate and then must be reduced back to ascorbate by the pathway described, to be reused as ascorbate. One can easily see how this mechanism and similar mechanisms could be overwhelmed by a toxic pathogen liberating free radicals or by an inflammatory cascade regardless of its cause.
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Re: How Does Vitamin C as Ascorbic Acid Enter Cells?

Post Number:#34  Post by majkinetor » Tue May 21, 2013 6:09 pm

I didn't get it quite right, this is how it happens:

Reduced glutathione (GSH) is a major tissue antioxidant that provides reducing equivalents for the glutathione peroxidase (GPx) catalyzed reduction of lipid hydroperoxides to their corresponding alcohols and hydrogen peroxide to water. In the GPx catalyzed reaction, the formation of a disulfide bond between two GSH molecules generates oxidized glutathione (GSSG). The enzyme glutathione reductase (GR) recycles GSSG to GSH with the simultaneous oxidation of β-nicotinamide adenine dinucleotide phosphate (β-NADPH2).

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

Post Number:#35  Post by ofonorow » Wed May 22, 2013 12:36 pm

Yes, which matches Dr. Cathcart's description of the understanding of the pathways.
Note he chose this as the example of a RATE LIMITED free radical scavanger.
THe point is that this is not a perpetual process, which is why Dr. Cathcart proposed his idea of a NON RATE
LIMITED free radical scavanger - high dose ascorbate. Cathcart pointed out that thea AA reduction product (DHA) is not harmful and there seems to be little issue as long as the ratio of AA to DHA remains high.

So your example is not proof that Ascorbate enters cells primarily as DHA.

I say that it is common sense that most ascorbate from the blood enters in the reduced (not oxidized) form, regulating the GLUT transmitters (if all else is true) to a secondary, almost backup function.
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Re: How Does Vitamin C as Ascorbic Acid Enter Cells?

Post Number:#36  Post by skyorbit » Wed May 22, 2013 9:48 pm

ofonorow wrote: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).


But the Body can make more GSH out of the proper Amino acids which comes from diet.

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

Post Number:#37  Post by ofonorow » Thu May 23, 2013 1:08 pm

Which is interesting, if Boyd Halley is correct, that this only happens with an intake of vitamin C. "The only way to increase intracellular GSH is vitamin C." Now we have had this argument before, but certainly, the raw amino acids and enzymes are important... A necessary (but maybe not sufficient) condition.
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Re: How Does Vitamin C as Ascorbic Acid Enter Cells?

Post Number:#38  Post by skyorbit » Sun May 26, 2013 10:15 pm

Boyd Halley is wrong. Have you read Dr Levy's book about GSH yet? NAC and Acytle L Carnatine in combination have been documented to increase GSH levels substantially with-out the need for other anti-oxident supplimentation. (ALC is a necessary co-factor in production of it.) As has SOD (being an anti-oxident in it's own right, like vitamin C, SOD helps to recycle GSH.).

Many of these questions you're asking I think can be resolved by you reading his book "GSH. Master Defender"

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

Post Number:#39  Post by ofonorow » Wed May 29, 2013 8:29 am

No I haven't read Dr. Levy's book, but will put it on my list. And I hate to pit Drs Haley and Levy, as Haley was an Emeritus professor in chemistry, and made that statement at that time he was selling his own product he hoped would increase GSH in cells. (The point was that he was testing and felt he would be able to prove that his product performed the same function has vitamin C - but he was shut down.)

We have also discussed the paper that I believe Haley relied on, the obvious heavy weight GSH expert (name escapes me) who made basically the same statement.

It is obviously a very important point, and apparently does rely on the antioxidant status inside the cell.

Will NAC (building blocks) + Acytl-L-carnitine increase GSH without vitamin C? That is the question.

My memory may be faulty - (the lectures were supposed to be released on DVD). But if I remember correctly, I doubt Haley was wrong about this.
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Re: How Does Vitamin C as Ascorbic Acid Enter Cells?

Post Number:#40  Post by skyorbit » Wed May 29, 2013 8:15 pm

NAC is the main building block (other amino acids needed are very ready in the body) and Acytl-L-carnitine is an important catalist.

All I know is, in his book he has citations of about 12 or so different nutrients that can increase GSH blood level serums that are NOT Vitamin C.
But he makes special mention of an NAC and ALC combination that be documented greatly increase GSH levels.

Certainly vitamin C can do it too, by donating electrons to help recycle preexisting GSH that the body has already made. In this way SOD, ALA and Vitamin E (although not a well) can also do what Vitamin C does in regards to GSH. VC isn't a a cofactor or ingredient in making the initial GSH molecule. It's synergy with GSH lies in their mutual recycling of each other.

No I haven't read Dr. Levy's book, but will put it on my list.


Dude, it's 80 pages. It'll take you less then an hour to read the whole thing.

Tracy

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

Post Number:#41  Post by majkinetor » Thu May 30, 2013 11:11 am

Yeah, I guess there are real quacks too on alternative side...
I already explained numerous times and gave number of references that GSH main replenisher is NAC (which is used in clinical practice to deal with drug toxicities that cause liver failure).

I don't have problem with statement that C recycles GSH, i have the problem with part that it is "the only" substance that does that. This is obvious nonsense and I don't know why do people even discuss it.

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

Post Number:#42  Post by ofonorow » Fri May 31, 2013 11:05 am

Lets see, Boyd Halley is an emeritus professor of Chemistry, and you sir, are.. what? Please enlighten us.

We did discuss this at length herehttp://www.vitamincfoundation.org/forum/viewtopic.php?f=11&t=10525&hilit=GSH+and+Halley&start=15 and I found the links to the Dr. Alton Meister papers, the "heavy weight" on GSH, who wrote these two papers.


Glutathione-Ascorbic Acid Antioxidant System in Animals
http://www.jbc.org/content/269/13/9397.full.pdf+html

Glutathione Metabolism and Its Selective Modification
http://www.jbc.org/content/263/33/17205.full.pdf
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Re: How Does Vitamin C as Ascorbic Acid Enter Cells?

Post Number:#43  Post by ofonorow » Sat Jun 01, 2013 11:56 am

Some interesting quotes from the second Alton Miester overview paper reviewing GSH metabolish.

Administration of cysteine may increase cellular levels of GSH, but even moderate doses of L-cysteine are toxic.


After a discussion of a pathway that would create/result in cysteine...

This thiazolidine is readily transported; its administration to mice stimulates GSH synthesis and protects against acetaminophen tox-icity. Brain GSH levels are only slightly increased after giving the thiazolidine; cysteine levels increase about 3-fold.


Cysteine delivery systems are limited by feedback inhibition of y- glutamylcysteine synthetase by GSH, but this may be bypassed by administration of substrate of GSH synthetase.
.
.
Procedures that increase the levels of the synthetases are also of interest. Ultimately, one may consider
the idea of increasing enzyme levels by gene therapy.



Administration of GSH leads to small increases in GSH levels, which may be ascribed to extracellular GSH breakdown, transport of the products, and intracellular synthesis of GSH.


Very interesting. Clarified understand of the how/why GSH is a "chelator" and much discussion of inhibitors, which reduce the amount of GSH in cells - which are apparently potent poisons. But at least as of 1988, even though he makes the following statement

Biochemical studies have elucidated the enzymatic bases of the functions of GSH. Of major importance has been the development of selective enzyme inhibitors which are potential therapeutic
agents. It is now possible to increase or to decrease cellular GSH levels and also to selectively inhibit
reactions involved in GSH metabolism.
\
other than that "thiazolidine" example, and "GSH monoesters"? (Perhaps N-acytl-cesteine?) , no other means of raising intraecullar GSH were apparently known.

http://www.jbc.org/content/263/33/17205.full.pdf
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Re: How Does Vitamin C as Ascorbic Acid Enter Cells?

Post Number:#44  Post by ofonorow » Sat Jun 01, 2013 12:58 pm

The first paper, after discussing all the maladies that are caused by depriving organisms of GSH -usually enzyme inhibitors - that poinst out that these maladies can be avoided by giving the organism ascorbic acid - vitamin C.

The discovery that the lethal and other effects of GSH deficiency can be prevented by administration of
ascorbate was made in the course of studies on newborn rats (4); later research on guinea pigs(12), which also do not synthesize ascorbate, and on adult mice (10, 13, 14), which do, has shown that there are significant interrelationships between GSH and ascorbate (15).



When newborn rats are made GSH-deficient by administration of BSO, they develop cellular damage in
liver, kidney, lung, and brain. They die within a few days. Death and tissue damage can be prevented
by administration of ascorbate (but not of dehydroascorbate).


The tissue ascorbate levels of GSH-deficient animals were greatly increased by giving ascorbate, as
expected, but surprisingly, giving ascorbate also led to higher GSH levels.


After pointing to studies that show GSH deficient lab rats develop cataracts..

Treatment of newborn rats with only two doses of BSO (on the 2nd and 3rd days of life) led to cataracts,
observed when the rats opened their eyes on days 14-16. The incidence of cataracts was 97% but was
only 9% in animals given both BSO and ascorbate (2mmol/kg/day).


Aside, these papers prevent pretty convincing evidence that cataracts are caused by a GSH deficiency (aka oxidative stress) and the reason that vitamin C has been shown to prevent cataracts may be its relation described here - to increase intra-cellular GSH. So if I wanted to prevent cataracts, in addition to ascorbate, I would consider Lypo-GSH.


GSH deficiency in adult mice is associated with decreased levels of phosphatidylcho-line in the lung and in the bronchoalveolar fluid; when ascorbate is given, lamellar body damage does not occur and the levels
of phosphatidylcholine increase by about 2-fold(13


Another aside. These are repeatable animal experiments that can be done with other substances, e.g. NAC and carntine. If these substances do generate GSH, it should be easy to demonstrate that these substances do in fact recycle or create GSH - as ascorbate has been shown to do. They should prevent these conditions that have been shown to appear after GSH depletion. Maybe such studies exist, and anyone cand find references, please post! (There seems to be a standard experiment in mice like this, GSH prevents Tylenol toxicity.)

Methods that increase cellular levels of GSH (10) include those based on administration of precursors
of substrates for y-glutamylcysteine synthetase and GSH synthetase, and of GSH derivatives such
as esters Cellular GSH levels may also be increased by increasing the levels of the synthetases; this has
been accomplished in microorganisms(70), and studies on animals are now feasible (see Refs. 71
and 72) and in progress.


These are important papers. GSH and ascorbate are two sides of a coin. They spare each other. But one can apparently work, at least for a time, without the other.

Ascorbate Deficiency in Guinea Pigs; Sparing of Ascorbate by GSH

It is well known that guinea pigs given an ascorbate-deficient diet develop scurvy and die within 21-24 days. There is a marked loss of weight (after the first week), which is followed by the appearance of
characteristic bone changes and hematomas. Treatment of such animals with GSH ester significantly delayed the onset of scurvy; there were no signs of scurvy after 40 days (33).

When guinea pigs receiving a scorbutic diet were given GSH ester, the tissue ascorbate
levels (as well as the GSH levels) were higher than those of saline-treated controls. The loss of
ascorbate was slowed in the presence of higher levels of GSH
, another in vivo result that supports
a role of GSH in the reduction of dehydroascorbate. The findings indicate that GSH, supplied as an ester, spares ascorbate.


First, I concede that there is an argument that "GSH esters" can increase GSH, at least as far as preventing ascorbate loss in tissues per the guinea pig/scurvy experiment. I am not now, but perhaps am becoming (after reading these papers) somewhat more knowledgeable about GSH.

I gather that the effect is less important without the other side of the coin - ascorbate. The pigs died, just more slowly.

While perhaps Halley's comment was incorrect "technically", from the macro perspective, so far it looks like Halley's comment still stands. (In those mice/tylenol experiments - the animals are making endogneous ascorbate and the tissues are saturated.)

So we are reduced to experiment in guinea pigs - to come to some equivalence with the human condition.

I have tried to email Dr Halley. Halley's videos equate oxidative stress with GSH inside cells. Less GSH, more stress. In terms of oxidative stress, unless the "GSH ester" is an antioxidant, without ascorbate, I still don't see how oxidative stress (GSH deficiency) can be rectified. I don't think it is cut and dried, and these papers tie AA and GSH tightly together.


http://www.jbc.org/content/269/13/9397.full.pdf+html
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Re: How Does Vitamin C as Ascorbic Acid Enter Cells?

Post Number:#45  Post by ofonorow » Sun Jun 02, 2013 1:32 pm

BIOLOGIC AND PHARMACOLOGIC REGULATION OF MAMMALIAN GLUTATHIONE SYNTHESIS
http://www.grupogales.com/admin_upload/documentos/pagina_medicina/1999-Glutathione.pdf

Another informative overview paper.

Administration of L-cysteine precursors and other strategies allow GSH levels to be maintained under conditions that would otherwise result in GSH depletion and cytotoxicity.


This may explain some of the confusion. Haley's statement was vitamin C was the only proven way to "increase", (not necessarily "maintain normal" GSH levels in cells that are depleted.)
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