In article <Pine.A18.104.22.1680505082737.8841A-100000 at itsa.ucsf.edu>, Bert Gold
<bgold at itsa.ucsf.edu> writes:
>April 22, 1996
>>Walking back from the bank to the hospital today I was prompted to
>buy several large juicy navel oranges. I've been eyeing oranges for many
>weeks now, but my wife and I have a long standing disagreement about
>who picks the best ones. I thought the oranges she chose at a fruit
>stand, just outside Half Moon Bay yesterday, were puny; she again
>suggested I always pick the oversized, dried up ones.
>Today, though, my oranges were winners: Sweet, juicy and large;
>just the way I like them.
>>In the news the past several days, as you've probably heard, Vitamin C
>requirements (RDAs, Required Daily Allowance, set by the National Research
>Council, the nation's highest scientific authority) for adult males have
>been revalued upward. Not modestly either: But three-fold, and still
>the upper limit is poorly defined. It seems an intramural researcher
>at NIH finally got the funding go ahead to do some of the experiments
>which Linus Pauling and Albert Szent-Gyorgyi always longed to do
>before the end of their lives, but were denied funding for.
>>It is notable that in this latest work (1), seven men in their twenties
>were fed increasing doses of Vitamin C after being starved for
>it in their diet. Although they never showed signs of scurvy,
>each volunteer did report feeling uncomfortable when deprived
>of Vitamin C. The NIH authors note that because the subjects
>of their study were young men in their 20's, the results are
>limited to this subject group.
>>The vivid image of Szent-Gyorgyi standing in front of Whitman Auditorium
>in Woods Hole holding a bottle of glyoxyl in one hand and Vitamin C
>in the other is permanently etched in my memory. I'll not easily
>forget the hypothesis of 'radical scavenging' which Szent-Gyorgyi
>put to us that day: He said that he and Pauling had been talking
>about the central importance of OXYGEN in human metabolism
>and explained that he had been concerned for a good deal of time about
>reactions generating singlet oxygen. These, produced in abundance
>during mitochondrial "charge transfer" in liver parenchyma, and other
>aerobically active tissues, must absorb electrons pairwise in order to
>avoid causing damage.
>>In 1931, Pauling discovered the superoxide radical, which, though
>produced in minute quantities as an unwanted byproduct of oxidative
>phosphorylation, has enormous destructive capacity if not defused (2).
>During lectures given at UC Berkeley in the 80s, Pauling paid
>tribute to the remarkable specificity of the enzymatic system that
>neutralizes it: Superoxide dismutase; at the same time, however,
>he noted that this enzyme does not defuse the lesser, but still significant
>intracellular destructive capacity of singlet oxygen or the hydroxide radical
>(and unkown to him at the time, the NO radical).
>>Superoxide dismutase transforms superoxide radicals to peroxide which can
>then be eliminated as water after the action of peroxidase and catalase.
>But what is the body to do with all the unpaired electrons such a process
>would generate? Szent-Gyorgyi told that oxygen itself could absorb unpaired
>electrons if only it were conjugated to carbon in the form of a double
>carbonyl: the simplest such compound being glyoxyl, commonly found in human
>liver, for this compound had sufficient electron delocalization to provide
>something of an electron sink. And, the supply of glyoxyl is renewable
>through the action of the glutathione-S-tranferase system, present in
>liver mitochondria. Further, Szent-Gyorgyi told us excitedly, two
>englishmen and a german, H.D. Dakin, H.W. Dudley and C. Neuberg had, in
>1913 discovered that methylated-glyoxyl could be transformed to a potent
>energy source itself, lactic acid, through the action of glyoxylase,
>which they discovered in that year. So, in one fell swoop, Szent-Gyorgyi
>had connected for us the relationship between oxygen radical and one
>carbon metabolism. I promise I will discuss this relationship in the
>next few weeks, when I write another essay, tentatively titled,
>Folic Acid and I.
>>In comments honoring Szent-Gyorgyi on the occasion of his 82nd
>birthday, Linus Pauling recalled Vitamin C's discovery by Szent-Gyorgyi
>in 1928. Pauling noted that Szent-Gyorgyi had written in 1939 (4) that
>although organisms were generally well adapted to their surroundings,
>that the destruction of the natural environment endangered that
>adapatation. "I have a strong faith in the perfection of the human
>body", Szent-Gyorgyi wrote in 1939, "and I think that vitamins are an
>important factor in its coordination with its surroundings. Vitamins,
>if properly understood and applied, will help us to reduce human suffering
>to an extent which the most fantastic mind would fail to imagine." (3)
>>On the day that I met him in Woods Hole, Szent-Gyorgyi told us he and Pauling
>(three Nobel prizes) between them suggested that significant increases
>in Vitamin C intake were almost certainly required by an adult body,
>perhaps especially at times when oxygen production was increased.
>Szent-Gyorgyi had insisted in a book he had written two years before,
>that Vitamin C, especially when complexed with manganese in
>the presence of oxygen, could synthesize a free radical form, as well and as
>easily as it could form a dehydroascorbate, oxidized form in the
>presence of copper or iron and in alliance with an enzyme he'd
>discovered in plants in 1931 and named 'ascorbic acid oxidase.'
>Szent-Gyorgyi insisted that it was in some sense the equilibrium between
>the various oxidized and reduced forms of ascorbate which provided its
>>And yet, this week, fully 18 years after the memorable talk by
>Szent-Gyorgyi which I just described, the Vitamin C RDA for men
>has been adjusted three-fold upward.
>>It makes me wonder at the brazen inefficiency of the research
>>The knowledge that both Linus and Albe died
>without ever attaining a modicum of funding for their final
>nutrition project confirms some of my worst fears about
>our ways of deciding what research is worthy in this
>>My hope in writing this is that our children will not suffer
>because of the lack of wisdom of their leaders in
>making decision about what to and what not to study.
>>(1) Levine, M.; Conry-Cantilena, C.; Wang, Y.; Welch, R.W.; Washko, P.W.;
>Dhariwal, K.R.; Park, J.B.; Lazarev, A.; Graumlich, J.G., King, J.;
>Cantilena, L.R. (1996) Vitamin C pharmacokinetics in healthy
>volunteers: Evidence for a recommended dietary allowance.
>Proc. Natl. Acad. Sci. USA; 93, 3704-3709.
>>(2) Marinacci, B. (1995) Linus Pauling in His Own Words, New York, Simon &
>>(3) Kaminer, B., ed. (1977) Search and Discovery, A tribute to Albert
>Szent-Gyorgyi, New York, Academic Press.
>>(4) Szent-Gyorgyi, A. (1939) On Oxidation, Fermentation, Vitamins, Health
>and Disease. Baltimore, Williams and Wilkins.
Pauling and Szent-Gyorgyi are my heros too, but neither a conspiracy or
scientific incompetence is necessary to explain delays in jumping to recommend
large doses of vitamin C. In fact chemistry, physiology etc. of ascorbic acid
has been under intense investigation over the last several decades. It is well
known that ascorbate, under some conditions acts a a pro-oxidant rather than an
antioxidant. As for all nutritional additives it is extremely difficult to
determine whether consumption of high levels of the pure product may cause
toxic effects which are neutralized by other components present in the natural
food sources. Do large doses of ascorbate protect, deplete, or block induction
of other antioxidants? I can probably find instances of all of these effects
in the literature of the past 5 years. In short, its not that simple. Evidence
for multiple benefits from increasing dietary intake of ascorbate and other
antioxidants by increased consumption of fruits and vegetables is very
convincing. The health benefits of ingesting large levels of purified
antioxidants of any kind are proving harder to analyse. Unfortunately we are
not yet to the point where we can usefully micro-manage our nutrition. Take
megadoses of vitamins if you chose, at your own risk, but many of us would
prefer to keep on eating our fruits and veggies.