Talk:Vitamin C

Removed during Big Cleanup

Image:Ascorbic_acid.png|right|frame|Chemical structure of vitamin C

Image:Ascorbic-acid-3D-vdW.png|thumb|right|200px|Model of the vitamin C (L-ascorbic acid) molecule. Black is carbon, red is Oxygen and white is Hydrogen

Image:GyorgyiNIH.jpg|thumb|200px|right|Albert Szent-Györgyi, pictured here in 1948, was awarded the 1937 Nobel Prize in Medicine for the discovery of vitamin C

Image:Rosa canina hips.jpg|right|thumb|Rose hips are a particularly rich source of vitamin C

Image:Goat.jpg|thumb|250px|Goats, like almost all animals, make their own vitamin C. An adult goat will manufacture more than 13,000 mg of vitamin C per day in normal health and as much as 100,000 mg daily when faced with life-threatening disease, trauma or stress.

Image:RedoxonVitaminC.jpg|thumb||right|Vitamin C is widely available in the form of tablets and powders. The Redoxon brand, produced by Hoffmann-La Roche was the first mass-produce synthetic vitamin C and was launched in 1934.

Pierre-Alain Gouanvic 00:05, 20 November 2007 (CST)Image:Ambersweet oranges.jpg|right|thumb|Citrus fruits were one of the first sources of vitamin C available to ship's surgeons. Pierre-Alain Gouanvic 04:38, 21 November 2007 (CST) Image:James lind.jpg|180px|right|thumb|James Lind (1716 – 1794), a British Royal Navy surgeon who, in 1774, identified that a quality in fruit prevented the disease of scurvy in what was the first recorded controlled experiment.

Image:Pauling Vit C Book Cover.jpg|right|thumb|250px|Linus Pauling's popular and influential book How to Live Longer and Feel Better, first published in 1986, advocated very high doses of vitamin C.

“

Serum and plasma vitamin C measurements do not correlate well with tissue levels while lymphocyte vitamin C levels provide the most accurate assessment of the true status of vitamin C stores and are not affected acutely by circadian rhythm or dietary changes.”

”

I don't see any real reason for having a seperate article on ascorbic acid, because vitamin C and ascborbic acid are one and the same, as pointed out in this article. Also, a bunch of chemical properties are already included, so I suggest removing sentences aluding to a non-existent ascorbic acid article. I'll leave that to the original authors though. I don't know how to wrap text around images, so the image I added is centered with nothing around it: a waste of space. Feel free to fix this. David E. Volk 16:37, 31 July 2007 (CDT)

Proposition: creation of the "Discovery of vitamin C"/"Discovery and history of vitamin C" page

The lengthy explanations on the history of vitamin c are interesting but could be displayed in a separate article. CZ has the article : "Discovery of pennicilin". I consider that "Discovery of vitamin C" would be an interesting page in its own right and could be the place to explore those problems surrounding vit. C's discovery and patenting and related issues (e.g. how scurvy was gradually accepted, how nascent globalisation of trade enabled the provision of never before seen amounts of vit. C in the northern latitudes, etc.). The page could also be more accurately called : "Discovery and history of vitamin C". A redirect from "Discovery of vitamin C" to "Discovery and history of vitamin C" or "History of vitamin C" could be used. Pierre-Alain Gouanvic 16:57, 13 November 2007 (CST)

Go for it. Chris Day (talk) 03:17, 19 November 2007 (CST)

The basic structure

The whole debate about recommended intakes is one thing, and of course Linus Pauling (and his 1971 paper) is at the center of the debate. Keeping an historical perspective is logical and useful. The fact that bowel tolerance varies in function of disease pertains to another logic, and to another section. Finally, the therapeutic uses are another section. No info will be suppressed in the process of structuring this article. Pierre-Alain Gouanvic 03:29, 19 November 2007 (CST)

...the 1974 paper. The reference has been included. Pierre-Alain Gouanvic 18:04, 19 November 2007 (CST)

The "Politics of Vitamin C" section

Was this a part of the original WP article? Because saying there is a conspiracy against Vitamin C seems awfully absurd (unless it actually is the case). Is it actually something that goes on? Also some things about the "Hypothesis" section seem equally dubious. --Robert W King 16:45, 19 November 2007 (CST)

It comes from WP. I agree. I'll work on that and will try to be constructive. Thanks for the input; I'll send you a notice when I it is done. Pierre-Alain Gouanvic 17:32, 19 November 2007 (CST)

A description of a nutrient includes its distribution in tissues and organs. This section will necessarily cover (part of) the debate on vitamin C requirements. Putting this in a separate "controversial" section would be biased.Pierre-Alain Gouanvic 21:08, 19 November 2007 (CST)

The "Vitamin C hypothesis" section

Many things in this section reflect a lack of understanding of who said what, etc. They will be moved in their respective sections on biosynthesis. Pierre-Alain Gouanvic 00:05, 20 November 2007 (CST)

In the following, all parts that are in italics are false, as we can judge by reading the biosynthesis section:

The fact that man possesses three of the four enzymes that animals employ to manufacture ascorbates in relatively large amounts, has led researchers such as Irwin Stone and Linus Pauling to hypothesize that man's ancestors once manufactured this substance in the body millions of years ago in quantities roughly estimated at 3,000–4,000 mg daily, but later lost the ability to do this through a chance of evolution. If true, this would mean that vitamin C was misnamed as a vitamin and is in fact a vital macronutrient like fat or carbohydrate. {Irwin Stone: "The Healing Factor"}

Dr. Hickey, of Manchester Metropolitan University, believes that man carries a mutated and ineffective form of the genetic machinery for manufacturing the fourth of the four enzymes used by all mammals to make ascorbic acid. Cosmic rays or a retrovirus could have caused this mutation, millions of years ago. {Hickey: "Ascorbate"} In humans the three surviving enzymes continue to produce the precursors to ascorbic acid but the process is incomplete and the body then disassembles them.

To be kept for future inclusion: the retrovirus hypothesis deserves its place; Irwin Stone's work, quoted in OMIM, too. Pierre-Alain Gouanvic 01:30, 20 November 2007 (CST)

Not useful in the intro, as it is in the chem box on its side

But the references will be useful:

also known by the chemical name of its principal form, L-ascorbic acid or simply ascorbic acid. Pierre-Alain Gouanvic 00:57, 21 November 2007 (CST)

Idem: The guidance provided by the United States of America and Canada for Dietary Reference Intake (DRI) recommends 90mg per day and no more than 2g per day (2000mg/day). Pierre-Alain Gouanvic 04:20, 21 November 2007 (CST)

Misplaced in the pharmacokinetics debate

Of course the following has to do with the debate:

Testing for ascorbate levels in the body Simple tests exist which measure levels of ascorbate ion in urine, serum or blood plasma. However, these tests do not accurately reflect actual tissue ascorbate levels. Reverse-phase high-performance liquid chromatography (HPLC) is used for determining vitamin C levels within lymphocytes and other tissue. It has been observed that while serum or blood plasma levels follow the circadian rhythm or short term dietary changes, levels within tissues are more stable and give a better determination of ascorbate availability within the organism. However, very few hospital laboratories are adequately equipped and trained to carry out such detailed analyses, and require samples to be analyzed in specialized laboratories.

... but this clearly deserves to be in the Distribution section. It will be important to provide a properly phrased link to the Distribution section. In +, the style doesn't have to be so colloquial. The example taken from diabetes is not especially useful: the article as it is now explains very clearly where, in the body, vitamin C is concentrated. Pierre-Alain Gouanvic 04:15, 21 November 2007 (CST)

General discussion on the acceptance of supplements

This burdens the page (see below, after the quote in italics). It's valid info, but it belongs to the "dietary supplement" page, some of it should really go in "consumer protection laws", "labelling", etc.

It will be possible to formulate concise and well referenced statements to replace this (there's only one ref, and its the conspiracy documentary. Worse than nothing, if it's not well supported (cf the comment by Robert W King, above)).

There exists research on the bias against Vitamin C in research, quoted by the famous Cochrane reviewer and researcher Harri Hemila: (http://www.cmaj.ca/cgi/eletters/174/7/937#4039)

Goodwin and Tangum (10) provided several examples to support the conclusion that there has been systematic bias against the concept that vitamins might be beneficial in levels higher than the minimum required to avoid classic deficiency diseases. Also, bias against vitamin C was documented by Richards (11,12) who compared the attitudes and arguments of physicians to three putative cancer medicines: 5-fluorouracil, interferon, and vitamin C. It seems that Pauling’s conclusions were dismissed because of the fundamental divergence with the traditional notion that the only purpose of vitamin C is to prevent scurvy (3) and not because of experimental findings. Evidently, carefully planned trials should be carried out to evaluate the potential role of high-dose therapeutic vitamin C on the common cold and cancer.

Removed section:

Advocacy arguments

Vitamin C advocates argue that there is a large body of scientific evidence that the vitamin has a wide range of health and therapeutic benefits but which they claim have been ignored. They claim the following factors affect the marketing and distribution of vitamin C, and the dissemination of information concerning the nutrient:

• There is increasing evidence of the applications and efficacy of vitamin C, but governmental agency dose and frequency of intake recommendations have remained relatively fixed. This has lead some researchers to challenge the recommendations.

• Research and the treatment approval process are so expensive, pharmaceutical companies rarely apply for approval of an unpatentable product. To do so without the protection of a patent would allow competitors to manufacture the product too, which would drive the price (and profit margin) down to a point much less desirable than the price point (and profit margin) of patentable products. The lower price would also reduce the likelihood of recuperating the company's exorbitant research funding and treatment approval costs. Vitamin C is not eligible for patenting because it is a natural substance, and because it has already been marketed to the public for some time. As of yet, no company has applied to the FDA (nor paid) for approval of vitamin C as a treatment for any disease.

• Companies selling a treatment product are not required to inform consumers or patients of other treatments, even if those treatments are more effective, less expensive, and have fewer side-effects. Medical practitioners are not required to inform their patients of treatments for which treatment approval has not been granted. This situation, coupled with the label censorship explained above makes it more difficult to keep the public informed about the benefits of and new discoveries concerning the applications and effective dosage levels of vitamin C.

• Matthias Rath and others point to low doses of vitamin C as the cause of the current epidemics of heart disease and cancer, and have termed the situation "a genocide", implying that health care providers (and particularly cardiologists and pharmaceutical companies) are aware of vitamin C's benefits and are deliberately seeking to block its acceptance as a therapeutic agent for financial gain.[111] He claims that governments have also colluded in this technology blockade by their expensive and bureaucratic systems of treatment approval which place barriers to new, inexpensive but not patentable approaches.

Reference 111:

1. ↑ http://www.vitamincproject.com/ A conspiracy against vitamin C supplements has been underway for over three decades

(the end)

Pierre-Alain Gouanvic 04:38, 21 November 2007 (CST)

Scurvy

In parallel with the redefinition of vitamin C ("it is not simply the antiscorbutic vitamin"; Cf section 2 on allowances, in particular), the redifinition of scurvy was also suggested, by more researchers than one would imagine (I guess). In other words, some have adopted the point of view that there's more than scurvy, while others have developped the point of view that scurvy is more than what James Lind described (and that we don't really have a non-arbitrary definition for scurvy). "Subclinical scurvy" and other paraphrases are not so uncommon amongst clinicians.

It would probably be wise to develop an article on scurvy that would account for this evolution of the term and of the notion. A practical benefit: it would make the vitamin C article more concise and more about vitamin C. A methodological advantage: it would allow for more detailed pathophysiological considerations : low vitamin C associated with

- high histamine (cf the article on Barlow's disease)

- capillary fragility (in many tissues)

- bone fragility

- weakness and fatigue (carnitine deficiency; cf article)

- etc.

... an article with direct clinical implications.

Then, the vitamin C article would more easily welcome even more useful informations on its physiological roles, and better explanations for the layperson.

Of course, both articles would link to each other.

Pierre-Alain Gouanvic 10:47, 21 November 2007 (CST)

• Axel Holst and Theodor Frolich--pioneers in the combat of scurvy

Tidsskr Nor Laegeforen. 2002 Jun 30;122(17):1686-7. [Axel Holst and Theodor Frolich--pioneers in the combat of scurvy] [Article in Norwegian] Norum KR, Grav HJ. ... Their findings were published in 1907 in the Journal of Hygiene, but caused scientific uproar since the concept of nutritional deficiencies was a novelty at the time. The crucial factor, Vitamin C, was discovered in 1930 by Albert Szent-Györgyi, for which he was rewarded the Nobel Prize. No prizes or proper recognition were awarded Holst and Frølich at the time. It took some 60 years before they due acclaim was given to them; the 1907 paper by Holst and Frølich is now considered the most important single contribution to elucidating the aetiology of scurvy. Pierre-Alain Gouanvic 17:48, 23 November 2007 (CST)

Fact check

In the description: "The D-enantiomer shows no biological activity." ambiguous. It can't be used as an enzyme cofactor, but it can be an electron donor (an antioxidant). It is not present in living things, if that's what it was supposed to mean. Pierre-Alain Gouanvic 11:44, 21 November 2007 (CST) "The active part of the substance is the ascorbate ion." Not a part. Pierre-Alain Gouanvic 11:46, 21 November 2007 (CST)

To do list

Section on evolution (biosynthesis)

At present, there are three considerations on the role and the impact of the inability to produce vit. C (in the article, Biosynthesis section). There exists other, possibly complementary, hypotheses (or "very suggestive observations") :

• 1. Retroviruses, Ascorbate, and Mutations, in the Evolution of Homo sapiens Jack J. ChallemA, * and E. Will Taylor.

high oxidative stress =) high DNA mutation rate =)high evolution rate

and :

retroviruses=)DNA mutations=)including GLO deficiency (hypoascorbemia)

Pierre-Alain Gouanvic 17:15, 22 November 2007 (CST)

• 2. Evolutionary significance of vitamin C biosynthesis in terrestrial vertebrates.

A Nandi, CK Mukhopadhyay, MK Ghosh, DJ … - Free Radic Biol Med, 1997

Evolution of vertebrates from aquatic medium to the terrestrial atmosphere containing high concentration of environmental oxygen was accompanied by tissue-specific expression of the gene for L-gulonolactone oxidase (LGO). ...

SOD vs GLO. When SOD increases, GLO decreases; ontogeny recapitulates phylogeny: high GLO during postnatal period (amphibians, early 4 tetrapods); "significantly higher plasma SOD and CAT activity in older individuals than in younger individuals. The induction in activity of SOD and CAT during human aging may be a compensatory response of the individual to an increased oxidative stress.

To evaluate further the nature of these enzymes in antioxidant defense, gene knockout mice deficient in copper-zinc superoxide dismutase (CuZnSOD) and GSHPx-1 have also been generated in our laboratory. These mice developed normally and showed no marked pathologic changes under normal physiologic conditions. The nature of antioxidant defense mechanisms: a lesson from transgenic studies. Environ Health Perspect. 1998 Oct;106 (they do have GLO.)

   The nature of antioxidant defense mechanisms: a lesson from transgenic studies.

Similarly, increased expression of extracellular SOD or glutathione peroxidase, as well as supplementation with SOD mimetics has been found to protect the CNS from a variety of neurotoxins (28, 29). In more simple models, overexpression of SOD and catalase significantly extended the lifespan of flies and worms ... Remarkably, up to 60% of the lifespan of SOD knockout and catalase knockout Drosophila can be restored by expression of SOD in only the motor neurons (32). Oxidative stress and nitration in neurodegeneration: Cause, effect, or association? http://www.jci.org/cgi/content/full/111/2/163

also see Ascorbic Acid: Biochemistry and Biomedical Cell Biology, James R. Harris, p. 157 (Dabrowski, 1994)

• 3. Vitamin C: the primate fertility factor? J MILLAR - Medical hypotheses, 1992
• 4. l-gulonolactone oxidase, a microsomal enzyme that catalyzes the terminal step in the biosynthesis of l-ascorbic acid is missing in most primates. Consequently, these organisms are prone to scurvy if the concentration of vitamin C in the diet falls. Paleopathological markers for the diagnosis of scurvy in ancient human skeletons have been described (22), but there is no paleopathological evidence of scurvy (or any other vitamin-specific dietary deficiency) among the Neanderthals or other fossil hominids. A molecule of l-ascorbic acid is consumed for each hydroxylation event (23). With an omnivorous dietary adaptation, especially a shift toward greater carnivory, there are periods when dietary vitamin C would either not be available or present only in reduced amounts. Recent humans, chimpanzees, and orangutans are omnivores; therefore, this difference in the posttranslational hydroxylation of osteocalcin compared to the herbivorous gorilla may relate to increased selective pressure to limit hydroxylation to counteract periods of low dietary vitamin C.

Osteocalcin protein sequences of Neanderthals and modern primates http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=15753298

• 5 (uric acid): Humans have higher serum levels of uric acid as compared with mice due to the loss of uricase activity.18 Uric acid may therefore aid in preserving ecSOD activity in humans at physiological levels. cf 2. Toward Understanding of Extracellular Superoxide Dismutase Regulation in Atherosclerosis http://atvb.ahajournals.org/cgi/content/full/22/9/1367
• These pseudogenes (gulo human & guinea pigs) are unique in that they are not accompanied by their functional gene in the genome, as are most pseudogenes Ascorbic Acid: Biochemistry and Biomedical Cell Biology, p35 (??)

Pseudogenes: Genes bearing close resemblance to known genes at different loci, but rendered non-functional by additions or deletions in structure that prevent normal transcription or translation. When lacking introns and containing a poly-A segment near the downstream end (as a result of reverse copying from processed nuclear RNA into double-stranded DNA), they are called processed genes. (MeSH)

• Z. "the primate L-gulono-gamma-lactone oxidase genes are a typical example of pseudogene" Random nucleotide substitutions in primate nonfunctional gene for L-gulono-gamma-lactone oxidase, the missing enzyme in L-ascorbic acid biosynthesis.Biochim Biophys Acta. 1999 Oct 18;1472(1-2):408-11. Ohta Y, Nishikimi M.

Section on "as an enzyme cofactor"

"Unlike other water-soluble vitamins, ascorbate is not specifically required for the functioning of ANY enzyme, and its exact physiological role is unkown" (then follows a rather long list of enzymes which use ascorbate). p158 (ibid) Pierre-Alain Gouanvic 17:56, 22 November 2007 (CST)

Section on the sociology of vitamin C

Criticism of animal models of disease

It has been argued that only primates, the Shionogi (ODS) rat, and guinea pigs are vitamin C-deficient species, that can be used in animal experiments to model human disease. This is a very radical issue. This absolutely has to be in the article. Pierre-Alain Gouanvic 17:42, 23 November 2007 (CST)

Mice unable to synthesize vitamin C should become valuable research tool, scientists say (May 16, 2000 -- No. 282):

""The value of the mice Dr. Maeda has made is that they are now in a sense ‘humanized.’ That means experiments with them can combine the dietary things that have long been possible with guinea pigs with the marvelous genetic experiments that are possible only with mice." (...) " The two scientists have been developing a deeper understanding of the genetic basis of atherosclerosis, commonly known as "hardening of the arteries." The condition involves fatty deposits building up on artery walls and restricting blood flow to the brain, heart and other parts of the body. A complex disease that affects people differently, atherosclerosis is the leading cause of death in the United States, and more than half the population suffers from it eventually."

Pierre-Alain Gouanvic 18:08, 23 November 2007 (CST)

Bias in vitamin C research (section)

Most medical interventions are submitted to a careful assessment of the evidence, where theoretical work, and clinical studies are weighted by competent experts in the field. The diffusion of the information on the theoretical work, and clinical studies in the media only plays a minor role, since patients will only receive what has been approved by specialists. With vitamin C supplements, the most sold supplements in the world, things are turned upside down. Research is published, mediatized, causes changes in public opinion (and doctor's opinions), it is later assessed by experts, often retracted or put in context (vit. C and cancer, oxalate, cataracts, so forth), but this doesn't get to the public, who remains with misconceptions (junk science).

• Research made by researchers who have specialized on (and sometimes patented) competing molecules

Definition of a conflict of interest in the context of non-patentable products versus patentable products (different from COI in the appraisal of patented products)

cf cataract, anticancer medications

The smart food market of innovation

Linus Pauling Institute vs Linus Pauling

Vitamin C has dose-dependent effects; the UL is criticized by experts; the RDA as well; neglecting this fact allows specialists in different fields of free radical research to continue to work on their own speciality, without setting priorities. The priorities of the market of innovation are different from citizen's priorities.

• Logical fallacies:

Research based on hypotheses but not on pathophysiology:

1. Oxalate (does oxalate excretion mean oxalate deposition? Also see hemodyalisis)

2. Oxidants are good, so antioxidants are bad

3. Vitamin C is part of a complex antioxidant machinery, so only cocktails should be studied

violation of scientific protocol

4. Whole foods are better than supplements, so vitamin deficiencies are not treated, but smart foods (patented products) are developped

5. The Fenton reaction (not adressing metal overload, or posing vitamin C (even when deficient) as a problem when metal overload is)

6. Antioxidants behaving as oxidants

In viruses and bacteria: part of their specific microbicidic activity, not proof of their dangers

Incomplete treatment of a deficiency; letting a deficiency state cause aberrations in redox metabolism

• Bandwagon fallacy: "Surfing" on misconceptions and media hype

Cf most of the above

• Appeal to fear: Playing with the fear of self-medication

Implies that it is better to let people in a deficient (subnormal) state than to let them self-medicate

Mistaking complementary measures with alternative measures

Treating the patient as more irresponsible than s/he is to push the argument of authority.

• Strawman arguments (answering the wrong question): Not taking in consideration markers of oxidative stress or tissue vitamin C status (no valid endpoints)

Reference : Proof versus plausibility (...), Hoffer, John. CMAJ; Hemila on Vit. C in colds and cancer: is the dosage issue publicly stated? Or is it only disclosed in medical journals ?

• Ad Hominem arguments:

Attacks to the reputation of Linus Pauling (senility, obsessive interests) remain in the public discourse, despite of proof of the contrary

The history of Vitamin C's appraisal is closely tied with the history of Linus Pauling's mental health appraisal

The virucididal, virus replication-inhibiting activity of vit. C remains largely unadressed, while Matthias Rath becomes an infamous celebrity.

• Denial

The evolutionary basis. "Nothing makes sense in biology except in the light of evolution." (Dobzhansky) The decline in vitamin C consumption in the evolution of man is by far the greatest dietary decline in his evolution (at least as far as vitamins are concerned; Cf Pauling, 1974, Milton (both already quoted)). Research doesn't reflect this fact.

Pierre-Alain Gouanvic 09:22, 24 November 2007 (CST) Pierre-Alain Gouanvic 11:23, 24 November 2007 (CST)

Clustering of diseases in categories

Presentation of the pathophysiological rationale for each section

• Viral diseases

Colds, others (cf Harakeh et al.)

• Cancer
• Toxics

Insecticides, heavy metals

• Liver diseases

Hepatitis, non-alcoholic fatty liver disease and carnitine-deficiency-associated diseases

• Brain diseases and psychiatry

Autism, stress-associated diseases (including libido), stroke, addictions

• Ocular diseases

cataract, others

• Heart disease

the Shionogi (ODS) rat and related items.

Halfway through; some formatting has to be done!

--Pierre-Alain Gouanvic 01:45, 26 November 2007 (CST)

Transfer to biosynthesis

... if it is not redundant:

Animal sources

The overwhelming majority of species of animals and plants synthesise their own vitamin C. Synthesis is achieved through a sequence of four enzyme driven steps, which convert glucose to ascorbic acid. It is carried out either in the kidneys, in reptiles and birds, or the liver, in mammals and perching birds. The last enzyme in the process, l-gulonolactone oxidase, cannot be made by humans because the gene for this enzyme is defective (Pseudogene ΨGULO). The loss of an enzyme concerned with ascorbic acid synthesis has occurred quite frequently in evolution and has affected most fish; many birds; some bats; guinea pigs; and most primates, including humans. The mutations have not been lethal because ascorbic acid is so prevalent in the surrounding food sources (it may be noted that many of these species' diet consists largely of fruit). Pierre-Alain Gouanvic 12:17, 24 November 2007 (CST)

Opening sentence unclear

Is Vitamin C the only required vitamin, and this only by a minority of animals, of which humans are one? Or Do the majority of animals require all the vitamins, and only a minority, including humans, only require vitamin C? Actually, neither of the above would seem to me to be true, but that's what the opening appears to say. Can someone clarify? Aleta Curry 15:22, 25 November 2007 (CST)

I would suggest something like:

Unlike other vitamins, which are required by the majority of animal species, vitamin C is only required by a minority of animal species, including humans and higher primates.

Would you say it's better?

Pierre-Alain Gouanvic 15:33, 25 November 2007 (CST)

Yes, much better, clear and to the point.Aleta Curry 15:38, 25 November 2007 (CST)

MUST be added to the article

The molecule was first called by Albert Szent-Gyorgyi "ignose, meaning ì don't know, or godnose, but the editor of the journal (...) did not appreciate such humor" Adult Scurvy J AM ACAD DERMATOL, DECEMBER 1999

Nomen est omen! Pierre-Alain Gouanvic 16:03, 25 November 2007 (CST)

From the early "politics of vitamin C" section

Since its discovery vitamin C has been considered a universal panacea by some, although this led to suspicions of it being overhyped by others.

In the 1960s Nobel-Prize winning chemist Linus Pauling, after contact with Irwin Stone, began actively promoting vitamin C as a means to greatly improve human health and resistance to disease. His book How to Live Longer and Feel Better was a bestseller and advocated taking more than 10,000 milligrams per day. It sold widely and many advocates today see its influence as the reason there was a marked downward trend in US heart disease from the early 1980s onwards.

Stone's work also informed the practise of Dr. Robert F. Cathcart III, in the 1970s and 1980s. He applied extremely large doses of ascorbate (300 grams = 0.66 pounds per day) to a wide range of viral diseases with successful results. Cathcart developed the concept of Bowel tolerance, the use of the onset of diarrhea as an indication of when the body's true requirement of ascorbic acid had been reached. He found that seriously ill people could often tolerate levels of tens of grams per day before their tolerance limit is reached.

Matthias Rath is a controversial German physician who once worked with Pauling. He is an active proponent and publicist for high dose vitamin C. He has published a theory that deaths from scurvy in humans during the ice age, when vitamin C was scarce, selected for individuals who could repair arteries with a layer of cholesterol. He theorises that, although eventually harmful, cholesterol lining of artery walls would be beneficial in that it would keep the individual alive until access to vitamin C allowed arterial damage to be repaired. Atherosclerosis is thus a vitamin C deficiency disease. Rath has also argued publicly that high doses of vitamin C can be effectively used against viral epidemics such as HIV, SARS and bird flu.

It has been suggested by some advocates that ascorbic acid is really a food group in its own right like carbohydrates or protein and should not be seen as a pharmaceutical or vitamin at all. {Irwin Stone: "The Healing Factor"}

transporters

For the SVCT transporters, I think you should mention the affinity and what that means in the context of biological concentrations. Also how does it compare to glut1 and the other gluts. For the GLUT transporters you only mention glut1. This is important when discussing the brain paradox because other gluts are in present in other tissues as well as all the SVCT's. The real key here, I presume, is that the affinity for GLUT1 is much higher than for all other transporters, even higher than SVCT?, and hence the brain gets much more of the available vitC. I'm guessing here but I know the GLUT1 affinity for glucose is much higher than for the other GLUTs, so I see no reason why the same is not true for vitC.

I'll analyze Wilson JX (2005). "Regulation of vitamin C transport". Annu. Rev. Nutr. 25: 105–25. PMID 16011461., reference #17, to try to address the issues that you raise. Thanks for emphacizing those problems! I was aware that GLUT types had to be dealt with. I'll provide the data on affinity, and show what it means.

The differences in insulin dependence of various tissues could play an important role in explaining many things, especially the brain paradox.

The paper you cite appears to conclude that "by transporting oxidized vitamin C, allows important organs to quickly store vitamin C in times of increased oxidative stress." This seems quite speculative, trying to correlate a fact with a putative reason (vitC is good for antioxidative properties). Is there a back up from later sources for such a comment? I can see the physiological reason for the high affinity for glucose, it's the only food source for neurons, but surely the high affinity for oxidised ascorbate is a secondary effect of the need for glucose? Or is the Km for oxidised ascorbate independent of the Km for glucose? Chris Day (talk) 03:02, 26 November 2007 (CST)

I don't known of any research that followed which reinforced those statements, but i think the reason for this is that researchers rarely utter finalistic arguments ("trying to correlate a fact with a putative reason", as you described).

The authors state that, at 60 mg of vit. C intake, there are vanishingly low levels of DHA; these levels only raise when oxidative stress tilts the AA/DHA balance. We could formulate things differently based on this.

The problem is that humans are the only species who consume, in comparison, vanishingly low amounts of vitamin C. Current pharmacokinetic data do not support the belief that gorillas excrete "expensive urine". Deriving broad conclusions about physiology based on dietary intakes set by (some) humans is a logical fallacy. I think that there's good evidence that, in other hypoascorbemic species, both AA and DHA are higher in the blood. Those are important data that i (or others) will have to provide.

Another issue is that the oxidation of ascorbic acid continually takes place, and research should identify what portion of it is recycled, what portion is transported in the brain, in urine, etc. As far as I know, nothing has been done to provide such a broad picture.

In terms of evolution, what would be the physiologic reason for taking either glucose, or an antioxidant precursor? I know of another instance where there is a trade-off between energy provision and antioxidant provision. Pyruvate can either be a substrate for oxidation or... a substrate for oxidation -- an antioxidant:

Secretion of pyruvate. An antioxidant defense of mammalian cells. J O'Donnell-Tormey et al. Journal of Experimental Medicine, Vol 165, 500-514

The rate of pyruvate accumulation was almost doubled in the presence of exogenous catalase, suggesting that released pyruvate functions as an antioxidant... Extracellular pyruvate was in equilibrium with intracellular stores. Thus, cells conditioned the extracellular medium with pyruvate at the expense of intracellular pyruvate, until homeostatic levels were attained in both compartments.

In other words: there is a coupling between oxidation and "antioxidation". The pyruvate used to eliminate oxidants is not used to produce oxidants through energy metabolism; the antioxidant glucose derivative (ascorbate) that is transported competes with glucose, a source of oxidants.

There's a similar interplay with glutamate: glutamate, the major excitatory transmitter, either causes the production of potentially toxic levels of oxidants (eventually leading to excitotoxicity) or is allocated to glutathione synthesis (GLU-CYS-GLY). Glutamate transport is the crucial issue here. There's also a coupling between ascorbate transport and glutamate transport in the brain (heteroexchange). Fascinating and enlightening phenomenon. Some references explore the pheomenon; this definitely deserves to be clearly put in the article.

First, I'll analyse closely the most relevant literature to get a clear picture, and perhaps these considerations will look more like reasonable inferences and less like personal insights?

Oh, the authors of the study also raise the possiblity that catecholamies could be involved (vit C is involved in catecholamine synthesis). They give much more importance to the antioxidant role of vit. C, however : (concluding sentence of the abstract:) "These results have implications for increasing antioxidant potential in the central nervous system." No mention of catecholamines.

Also, why the transport of oxidized vitamin C rather than vitamin C?

In order to get rid of the finalistic argument, it could be useful to show that this entrapment is an evolutionarily conserved method to keep vitamin C in compartments, without the risks associated with the maintenance of transporters, such as SVCTs, which could allow vit. C to leave compartments although it let it in in the first place. The given compartment keeps as much vitamin C as it can recycle (from DHA). The PNAS study revealed that high AA levels could be reached with DHA administration, without evidence of an oxidant overload.

--Pierre-Alain Gouanvic 15:35, 26 November 2007 (CST)

i don't have time to digest all your info here but with respect to "Also, why the transport of oxidized vitamin C rather than vitamin C?"; this is an interesting question. Without reading around the topic my assumption is that SVCT's are the primary transporter and GLUT's are a secondary transporter. I assume that the oxidised form is quite similar to the glucose topology whereas the vit C is not. If true, then the oxidised vitC affinity for GLUT's might be proportional to the glucose affinity and GLUT1 might be serendipidously more efficient at transporting the oxidised vitC than the equivalent SVCT. Possibly the brain SVCT is even not present due to its function being lost in that tissue in preference to GLUT1 function? (excuse all the wild speculation but this is not my area.) So far, this section raises far more questions for me than being informative. Now, after all my wild speculation, I'll try and find the real kinetics and expression patterns for these transporters. I'll read the review you link to above too. Hopefully we can find some more concrete reviews with regard to the brain paradox and the significance of GLUT1 in that role. Chris Day (talk) 16:18, 26 November 2007 (CST)

I'm getting my GLUT transporters mixed up, GLUT1 is not brain specific and not the one with the very low Km. After a bit of reading is is clear that not all GLUT's can transport oxidised vitC; only GLUT1,3 and 4. One thing i had not got straight was that SVCT is specific for reduced form. I found an interesting paper by Montecinos V, et al. Vitamin C is an essential antioxidant that enhances survival of oxidatively stressed human vascular endothelial cells in the presence of a vast molar excess of glutathione. J Biol Chem. 2007 May 25;282(21):15506-15. Epub 2007 Apr 2. PMID 17403685. More thoughts later. Chris Day (talk) 17:47, 26 November 2007 (CST)

The paper by Wilson is very dense.

So, yes, SVCTs and GLUTs transport AA and DHAA, respectively. I think that the following, another paper by Vera & al (the one you suggest is one of the latest of great researches by Vera and colleagues), is very useful: Nualart FJ et al Recycling of vitamin C by a bystander effect. J Biol Chem. 2003 Mar 21;278(12):10128-33. Epub 2002 Nov 14.

PMID: 12435736.

I hope you don't mind if I quote extensively; I also used bold characters which might look a little "agressive". Sorry!

Our data directly address the apparent paradox that although all human cells have the capacity to transport oxidized vitamin C, dehydroascorbic acid represents a very small fraction of total ascorbate in vivo (2, 31). (...) Using in vitro transport assays under strictly controlled conditions to avoid the uncontrolled oxidation of ascorbic acid, we have shown absence of functional ascorbic acid transporters in a number of cells of human origin (10-12, 15). We have recently extended this analysis to normal and neoplastic cells and cells lines derived from human prostate and breast (this study)2 and found that they transport dehydroascorbic acid efficiently through facilitative glucose transporters. Furthermore, our studies in vivo suggest that oxidized vitamin C may cross the blood-brain barrier (16). Why, then, if all human cells express dehydroascorbic acid transporters, is there no detectable dehydroascorbic acid in blood? We reason that this may be related to the chemical properties of the different forms of vitamin C. Although ascorbic acid appears to be stable in vivo, in solution dehydroascorbic acid undergoes hydrolysis with an estimated half-life of less than 1 min (10, 38-41). The hydrolysis is an irreversible process, which if it where to occur in vivo, would imply a vast consumption of vitamin C. This is an issue of physiological significance because humans are unable to synthesize vitamin C and must obtain the vitamin from external sources in the diet. The absence of vitamin C in the diet leads to the development of scurvy with its associated problems and ultimately death. Although there has been some controversy regarding the definition of the optimal daily requirements of vitamin C in humans in exact physiological terms (42, 43), it is clear that small daily amounts of vitamin C in the diet are sufficient for the maintenance of a "normal" human physiology. It is therefore evident that the salvage of vitamin C in vivo through continuous recycling could be central to the maintenance of low daily requirements of the vitamin. This is an issue that has been addressed in the case of the recycling of vitamin C by human erythrocytes and its effect on the antioxidant reserve of whole blood (44, 45). Our present data extend these previous observations by indicating that the dehydroascorbic acid generated locally by oxidation of ascorbic acid can be immediately transported intracellularly and reduced back to ascorbic acid by neighboring cells. Moreover, our in vitro data indicate that the bystander effect is operative in the presence of physiological concentrations of glucose, and we have preliminary evidence indicating that the bystander effect may be functional in vivo (46). Thus, the bystander effect may provide cells with an efficient system for the recycling and salvage of vitamin C.

This certainly must be taken into account when analyzing affinities and concentrations.

--Pierre-Alain Gouanvic 20:40, 26 November 2007 (CST)

I'll read that one too. Just for onlookers, I'm not proposing to go into detail like this in the article, but to get an accurate redux of the current knowledge it is important to know exactly what the data is in these papers as well as the conclusions they are drawing from their data. Hopefully the final paragraph will be accessible to all. Chris Day (talk) 23:30, 26 November 2007 (CST)