IV.A.3. - Vitamin C
delineating the history of a vitamin, we can often recognize four
chronological phases. First, there is the description of a disease
of unknown etiology, and second, there is the description of an
empirical cure for the disease. Following this step, and often
closely associated with it, is the identification of the curative
factor which perforce then becomes known as a vitamin.
In the fourth phase the mode of action of the vitamin in preventing
the deficiency disease is characterized.
history of vitamin C (ascorbic acid) conforms to this general
pattern. The characterization of the deficiency disease (scurvy)
and the empirical discovery of a cure for it are, properly speaking,
a part of the history of scurvy and have been dealt with elsewhere
in this work. But this chapter is concerned with the subsequent
history of the antiscorbutic factor, which conveniently presents
itself in three chronological stages: (1) the somewhat ill-defined
and open-ended period from the beginning of the nineteenth
century to the 1920s when the vitamin had the existence
of an "unrevealed presence" and was known to exist only
because of its preventive influence on the disease scurvy (just
as, during the same period, the perturber of Uranus was known
to exist long before the "discovery" of the planet Pluto);
(2) the 1920s and the 1930s, when vitamin C was named, isolated,
and its molecular structure revealed (in that order); and (3)
the modern post-1940 period, with its emphasis on the characterization
of the biochemical role of vitamin C in preventing scurvy and,
more recently, the debatable "extra-antiscorbutic" roles
sometimes attributed to it.
early history of vitamin C cannot readily be separated from that
of the demise of scurvy. By the beginning of the nineteenth century
it was generally accepted that it was possible to prevent and
cure scurvy by the use of citrus fruits: James Linds contribution
in establishing this belief was of paramount significance. But
it was in essence a pharmacological concept rather than a nutritional
one; the belief that the citrus fruits were replacing a missing
dietary component would have been alien to medical thought at
the beginning of the nineteenth century; even Lind himself did
not regard fruit and vegetables as obligatory dietary principles
in the prevention of scurvy. In other words, not until the end
of the nineteenth century was there any general acceptance that
scurvy was a deficiency disease resulting from a lack of a specific
dietary principle and that the disease could be prevented or cured
by appropriate dietary manipulation. Moreover, even this acceptance
was complicated by the advent of the germ theory of disease which,
some have argued, caused reversion to an infection theory to explain
of the earliest thinkers to discuss these new ideas was George
Budd (180882), Professor of Medicine at Kings College,
London although as K. C. Carter has indicated, Budd should
perhaps be regarded as a developer rather than as an innovator
of the "deficiency disease theory" (Hughes 1973; Carter
1977). In 1842, Budd published in the London Medical Gazette
a series of articles entitled "Disorders Resulting from Defective
Nutriment." He described "three different forms of disease
which are already traced to defective nutriment" and argued
that such conditions resulted from the absence of dietary factor(s)
other than carbohydrate, fat, and protein, and that the absence
of each of these specific factors would be associated with a specific
disease an idea that lay in abeyance for some 40 years
until experimentally proved by N. Lunin. There can be little doubt
that the three diseases described by Budd were avitaminoses A,
C, and D.
J. Harris, himself a significant figure in the later history of
vitamin C, aptly described Budd as "the prophet Budd"
and referred to an article in which Budd expressed the belief
that scurvy was due to the "lack of an essential element
which it is hardly too sanguine to state will be discovered by
organic chemistry or the experiments of physiologists in a not
too distant future" (Budd 1840; Harris 1937: 8).
happened, however, to fulfill Budds prophesy until the beginning
of the twentieth century. In 1907, A. Holst and T. Fröhlich
of Norway reported experiments in which they had demonstrated
that scurvy could be induced in guinea pigs and cured by dietary
manipulation (Holst and Fröhlich 1907; Wilson 1975). They
used guinea pigs to assess the antiscorbutic value of different
foodstuffs and to show the thermolabile nature of the antiscorbutic
factor. At the same time there were parallel, but independent,
developments in the general theory of vitamin deficiency diseases.
F. G. Hopkins, developing earlier work by Lunin, C. A. Pekelharing,
W. Stepp, and others, in 1912 published his classic paper in which
he demonstrated the presence of growth factors in milk and showed
their essential dietary nature (Hopkins 1912); in the same year,
Casimir Funk introduced his "vitamin hypothesis," in
which he attributed scurvy to the absence of an "anti-scurvy
vitamine" (Harris 1937: 121).
use of the guinea pig assay technique for the assessment of the
antiscorbutic factor was extended, and in 1917, H. Chick and M.
Hume published an important paper in which they reported the factors
distribution in a number of foodstuffs (Chick and Hume 1917).
The following year A. Harden and S. S. Zilva published their fractionation
studies on lemon juice, in which they demonstrated that the antiscorbutic
potency was not attributable (as had been suggested by earlier
workers) to the citric acid content (Harden and Zilva 1918). The
year after that, J. C. Drummond designated the factor "Water
soluble C" (Drummond 1919).
of Vitamin C
now began in earnest to identify and isolate the antiscorbutic
factor. The Medical Research Councils 1932 publication Vitamins:
A Survey of Present Knowledge may be referred to for a detailed
account of the large number of papers published during the 1920s
on what was by then known as "vitamin C." Foremost in
these early efforts was Zilva, working at the Lister Institute,
London. The essential feature of Zilvas procedure was the
precipitation of the factor with basic lead acetate after removal
of the bulk of the other organic acids with calcium carbonate.
He applied this technique to a variety of sources, such as lemon
juice and swede (rutabaga) tissues, and he succeeded in increasing
the concentration of the antiscorbutic factor some 200 to 300
times (Hughes 1983).
workers were similarly occupied, notably N. Bezssonoff in France
and C. G. King in the United States. King has stated that during
this period "many investigators had abandoned or failed to
publish their work for various reasons." He referred, specifically,
to Karl Link of Wisconsin, who had prepared several grams of crude
calcium ascorbate during the 1920s but carried his work no further
because of lack of financial support (King 1953).
purest of these early "concentrates" still contained
much impurity, and it was not until 1932 that W. A. Waugh and
King published their paper "The Isolation and Identification
of Vitamin C," which included a photograph of vitamin C crystals
(Waugh and King 1932).
attempts to isolate and characterize vitamin C were paralleled
by two separate, but nevertheless highly relevant, developments
in related areas. J. Tillmans and P. Hirsch, German government
chemists, extensively studied the capacity of lemon juice preparations
to reduce the redox dye 2,6-dichlorophenolindophenol, and they
claimed that the reducing power of their preparations was always
in proportion to their antiscorbutic potency; the indophenol dye
technique later became a standard method for the assay of vitamin
C. Zilva, however, disagreed with the German findings and appears,
at that point, to have been diverted from his main endeavor by
an attempt to disprove them (Zilva 1932).
other significant development at this time was Albert Szent-Györgyis
isolation of hexuronic acid. Szent-Györgyi, a Hungarian biochemist
working on plant respiration systems at Groningen in Holland,
became interested in a reducing compound present in his preparations.
Hopkins invited him to Cambridge to extend his studies, and in
1927, Szent-Györgyi isolated his "Groningen reducing
agent" in a crystalline, from oranges, lemons, cabbages,
and adrenal glands (Szent-Györgyi 1928).
proposed to name his crystalline sample "ignose"
thus indicating its apparent relationship to sugars while at the
same time underlining his ignorance of its true nature. But Harden,
the editor of the Biochemical Journal at the time, according
to Szent-Györgyi, "did not like jokes and reprimanded
me." A second suggestion "godnose" was judged to
be equally unacceptable. Szent-Györgyi finally agreed to
accept Hardens somewhat more prosaic suggestion "hexuronic
acid" "since it had 6 Cs and was acidic"
(Szent-Györgyi 1963: 114).
acid was a strongly reducing compound. So, too, according to Tillmans
and Hirsch, was the antiscorbutic substance (vitamin C). The suggestion
that hexuronic acid and vitamin C were actually one and the same
substance appeared in print in 1932 in papers by both J. L. Svirbely
and Szent-Györgyi and by Waugh and King, but there can be
little doubt that the idea had been mooted some years previously.
Who first made the suggestion is, however, unclear, and even the
main participants in the drama later appeared uncertain and confused.
King (1953) claimed that it was E. C. Kendall in 1929, but according
to Hopkins (reported by King) it was Harris in 1928 (King 1953)
and he had, in any case, already attributed the idea to
Tillmans and Hirsch (Harris 1937: 95). But E. L. Hirst (a member
of the team later involved in chemical studies on the structure
of vitamin C) named Waugh and King (Hirst 1953: 413).
had already, in 1928, sent a sample of Szent-Györgyis
hexuronic acid to Zilva for comments on its vitamin C potency.
According to King, Hopkins was disturbed because Zilva (who, naturally
perhaps, was reluctant to admit that his "antiscorbutic preparations"
were in reality identical with hexuronic acid) had replied that
the sample was not vitamin C, but did so without reporting the
evidence of his tests (King 1953).
1932, however, evidence in favor of the identity of hexuronic
acid as vitamin C was substantial. Waugh and King had shown that
their "crystalline vitamin C" cured scurvy in guinea
pigs (Waugh and King 1932), and earlier the same year, Svirbely
and Szent-Györgyi (now working in his native Hungary) had
described the antiscorbutic potency of a sample of "hexuronic
acid" isolated from adrenal glands (Svirbely and Szent-Györgyi
1933, in a single-sentence letter in Nature, Szent-Györgyi
and W. N. Haworth drew attention to the chemical inaptness of
the term "hexuronic acid" and suggested the term "ascorbic
acid," thus formally acknowledging the antiscorbutic nature
of the compound. Harris and his colleagues at Cambridge demonstrated
the positive correlation between the hexuronic acid content and
the antiscorbutic potency in a wide range of foodstuffs and published
a highly convincing "eight-point" proof of the identity
of the two substances.
three most important points were as follows: (1) Hexuronic acid
paralleled antiscorbutic potency; (2) destruction of hexuronic
acid by heat or by aeration was accompanied by a corresponding
fall in the antiscorbutic activity; and (3) hexuronic acid disappeared
from the organs of scorbutic guinea pigs (Birch, Harris, and Ray
1933). There could now be little doubt that hexuronic acid (Tillmans
and Hirschs reducing compound) and vitamin C were one and
the same substance.
situation was not without its human aspects, and even today the
question of priority in the discovery of vitamin C still elicits
discussion. "The identification of vitamin C is one of the
strangest episodes in the history of vitamins," wrote T.
H. Jukes in commenting on the appearance in 1987 of a book by
R. W. Moss that placed, in Jukess opinion, too great an
emphasis on Szent-Györgyis contribution (Moss 1987;
Jukes 1988: 1290). Moss had implied that King had rushed off his
claim for the identity of vitamin C and hexuronic acid after it
became clear to him that Szent-Györgyi intended making the
same point in a note to Nature a situation curiously
reminiscent of the suggestion that Charles Darwin behaved similarly
on learning in 1858 that Alfred Russel Wallace was about to publish
his theory of evolution.
emphasis now shifted to the elucidation of the structure of vitamin
C. Haworth, a Birmingham (U.K.) chemist, had received from Szent-Györgyi
a sample of his "hexuronic acid," and in 1933, in a
series of impressive papers, the Birmingham chemist, using both
degradative and synthetic procedures, described the structure
of the molecule (Hughes 1983). The molecule was synthesized simultaneously,
but independently, by T. Reichstein in Switzerland and by Haworth
and his colleagues in Birmingham, both groups using essentially
the same method.
synthesis which, as it later emerged, was quite different
from the biosynthetic pathway was based on the production
of xylosone from xylose and its conversion with cyanide to an
imino intermediate that, on hydrolysis, gave ascorbic acid. The
Swiss group published their results just ahead of the Birmingham
workers (Ault et al. 1933, Reichstein, Grussner, and Oppenheimer
1933). The picture was completed the following year when the Birmingham
workers joined forces with Zilva to demonstrate that synthetic
ascorbic acid produced at Birmingham had exactly the same antiscorbutic
potency as a highly purified "natural" sample from the
Lister Institute (Haworth, Hirst, and Zilva 1934).
annual report of the Chemical Society for 1933, with perhaps unnecessary
caution, stated that "although it seems extremely probable
that ascorbic acid is vitamin C . . . it cannot be said
that this is a certainty." Other were less circumspect. A.
L. Bacharach and E. L. Smith, addressing the Society of Public
Analysts and Other Chemists in November 1933, said that "Vitamin
C can now be identified with a sugar acid known as ascorbic acid. . . .
Contrary to expectation, it is the first vitamin not merely to
have assigned to it a definite molecular formula, but actually
to be synthesised by purely chemical means" (Hughes 1983).
Budd was correct in his 1840 prophecy that both physiologists
and chemists could contribute to the identification of the "antiscorbutic
factor." But his "not too distant future" proved
to be a period of 93 years!
and Metabolism of Vitamin C
the end of the 1930s, serious research had commenced on the biological
role of vitamin C. In particular, biochemical reductionists sought
to explain the nature of the relationship between the clinical
manifestations of scurvy and the biochemical involvements of vitamin
C. It was recognized that vitamin C was a powerful biological
reductant, and there were early attempts to explain its nutritional
significance in terms of its involvement in oxidation-reduction
systems a major theme in prewar biochemistry. But the first
clear advance in the biochemistry of vitamin C came from studies
of its biosynthesis, and by the early 1950s, the pathway for its
formation from simple sugars had been worked out. L. W. Mapson
and a colleague at the Low Temperature Research Station at Cambridge
(U.K.) fed different possible precursor molecules to cress seedlings
and measured the formation of vitamin C. And in the United States,
King and co-workers used labeled glucose to chart the biosynthetic
pathway in rats (Mapson 1967: 36980).
biosynthetic pathway proved to be a comparatively simple one.
D-glucuronate (formed from glucose) is converted to L-gluconate
and then to L-gulono-gamma-lactone, which in turn is further reduced
(via L-xylo-hexulonolactone) to L-ascorbic acid (2-oxo-L-gulono-gamm-lactone).
The final enzymatic step is catalyzed by L-gulonolactone oxidase
(EC 184.108.40.206.) in the liver in evolutionarily "advanced"
species such as the cow, goat, rat, rabbit, and sheep and in the
kidney in other species such as the frog, snake, toad, and tortoise
and it is this enzyme that is lacking in those species
unable to synthesize vitamin C.
date, this biochemical "lesion" has been detected in
a small, and disparate, number of species higher primates
(including, of course, humans), guinea pigs, certain bats, birds,
insects, and fish (Chatterjee 1973; Sato and Uderfriend 1978).
Whether all these species are necessarily scurvy-prone is not
quite so clear. A survey of 34 species of New World microchiropteran
bats showed that L-gulonolactone oxidase was apparently absent
from the livers of all of them (and from the kidneys of at least
some of them), but nevertheless, the tissue levels of ascorbic
acid (even in species that were fish-eaters or insect-eaters)
were similar to those in species that could biosynthesize the
vitamin (Birney, Jenness, and Ayaz 1976).
finding would suggest that the vitamin was being synthesized in
organs other than the liver and kidney; or that the metabolic
requirement for it was remarkably low; or that there were extremely
efficient mechanism(s) for its protection against degradative
changes. The whole question of the evolutionary significance of
vitamin C in plants as well as in animals remains
a largely uncharted area.
rate of endogenous biosynthesis of vitamin C in those species
capable of producing the vitamin shows considerable interspecies
variation, ranging from 40 milligrams (mg) per kilogram (kg) body
weight daily for the dog to 275 for the mouse (Levine and Morita
1985). These values are well in excess of the amounts of the vitamin
required to prevent the appearance of scurvy in species unable
to synthesize it a finding that has frequently been used
to buttress the claim that vitamin C has a number of "extra-antiscorbutic"
roles requiring daily intakes well in excess of the recommended
total body pool of ascorbic acid in a 70 kg man has been estimated
at about 1.5 grams (g) (but according to Emil Ginter it could
be three times as great as this [Ginter 1980]), which is attainable
in most people by the sustained daily intake of 60 to 100 mg.
A daily intake of 10 mg vitamin C results in a body pool of about
350 mg. Scorbutic signs do not appear until the pool falls to
below 300 mg (Kallner 1981; "Experimental Scurvy" 1986).
(and less conveniently, leucocyte) concentrations of ascorbic
acid are often taken as an index of the body status of the vitamin.
The normal concentration range in the plasma of healthy persons
on an adequate plane of nutrition is 30 to 90 micromoles per liter
(mmol/L) (0.51.6 mg/100 ml). The Nutrition Canada Interpretive
Guidelines are often referred to in this respect; these guidelines
suggest that values between 11 and 23 mmol/L are indicative of
marginal deficiency and that values below 11 mmol/L point to frank
severe deficiency but differences of sex, race, metabolism,
smoking habits, and, particularly, of age (factors known to influence
plasma ascorbic acid concentrations) reduce the validity of such
a generalization (Basu and Schorah 1981; Hughes 1981b).
a period of vitamin C depletion there is a comparatively rapid
loss of vitamin C (a reduction of about 3 percent in the body
pool daily) resulting from the continued catabolism of the vitamin
and the excretion of its breakdown products in the urine. In humans,
the main pathway identified involves the conversion of the ascorbic
acid to dehydroascorbic acid, diketogulonic acid, and oxalic acid
(in that order), with the two latter compounds accounting for
the bulk of the urinary excretion of breakdown products. Smaller
amounts of other metabolites, such as ascorbic acid-2-sulphate
also occur, and in the guinea pig there is substantial conversion
of part of the ascorbic acid to respiratory CO2. It has sometimes
been argued that the excess formation of these catabolites (particularly
oxalic acid) should signify caution in the intake of amounts of
vitamin C substantially in excess of the amount required to prevent
Role of Vitamin C
was noted in the early experiments of Holst and Fröhlich,
and confirmed by many subsequent workers, that defective formation
of connective tissue was a primary pathological feature of experimental
scurvy, and at one time it was believed that this lesion could
account for most of the known pathological sequelae of the disease
the petechial hemorrhages, the breakdown of gum tissue,
and the impairment of wound repair tissue. Attempts to characterize
the biochemical modus operandi of vitamin C in preventing scurvy,
therefore, centered initially on the metabolism of collagen
the essential glycoprotein component responsible for imparting
strength to connective tissue.
the 1970s, there was suggestive evidence that the biochemical
lesion was located in the hydroxylation of the proline and lysine
components of the collagen polypeptide and that vitamin C had
an essential role in the process (Barnes and Kodicek 1972). The
hydroxylases involved in collagen biosynthesis (prolyl 4-hydroxylase,
prolyl 3-hydroxylase, and lysyl hydroxylase) require ferrous iron
as a cofactor, and it appears that vitamin C, a powerful biological
reductant, has an almost obligatory role in maintaining the ferrous
iron in the reduced form. Thus emerged a simplistic and reductionist
explanation for the role of vitamin C in preventing the emergence
of the main clinical features of scurvy.
although there can be little doubt that vitamin C plays a critical
role in the biosynthesis of collagen, recent studies have suggested
that the simple "defective hydroxylation" theory is,
perhaps, not the complete story. Studies have indicated that the
activity of prolyl hydroxylase and the formation of collagens
by fibroblast cultures is not influenced by ascorbic acid; furthermore,
ascorbic acid deficiency does not always result in severe underhydroxylation
of collagen in scorbutic guinea pigs (Englard and Seifter 1986).
is increasing evidence that vitamin C may also influence the formation
of connective tissue by modifying the nature and formation of
the extracellular matrix molecules (Vitamin C Regulation 1990).
B. Peterkofsky (1991) has recently suggested that the role of
vitamin C in collagen biosynthesis is a dual one a direct
influence on collagen synthesis and an indirect one (mediated
perhaps via appetite) on proteoglycan formation.
complement component Clq, which has a central role in disease
resistance, contains a collagen-like segment that is rich in hydroxyproline,
and it has been suggested that this segment could offer a link
with the putative anti-infective powers widely suggested for vitamin
C (Pauling 1976; see also the section on megatherapy). Studies
over the last 15 years, however, have failed to demonstrate that
the complement system, unlike connective tissue collagen, reflects
vitamin C availability (Thomas and Holt 1978; Johnston 1991).
Indeed, the belief that vitamin C had anti-infection powers probably
stemmed from reports by Harris in 1937 of lowered vitamin C in
persons suffering from certain diseases, particularly tuberculosis.
the 1960s and the 1970s, however, some 25 epidemiological studies
were completed in different parts of the world to assess the validity
of claims that vitamin C had anti-infection powers, particularly
with respect to the common cold. The general conclusion drawn
from the results of these studies was that the evidence for a
protective/curative role for vitamin C in the common cold was
far from convincing (Hughes 1981b: 226; Carpenter 1986:
is accumulating evidence, however, that vitamin C may have additional
involvements in a range of enzymatic changes unrelated to the
formation of collagen. There are three systems of considerable
physiological significance in which vitamin C plays an important,
and possibly obligatory, role: (1) as the immediate donor for
dopamine B-hydroxylase, a key reaction in the conversion of tyrosine
to norepinephrine (Englard and Seifter 1986; Fleming and Kent
1991); (2) in the peptidylglycine alpha-amidating monooxygenase
system, whereby peptidyl carboxyl-terminal residues are amidated,
a process that requires molecular oxygen, copper, and ascorbate
and is important in the biosynthesis of a number of neuroendocrine
peptides (Englard and Seifter 1986; Eipper and Mains 1991); (3)
in the hydroxylation reactions in the biosynthesis of carnitine
from lysine and methionine (Englard and Seifter 1986; Rebouche
exact physiological significance of these and other reactions
vis-à-vis the clinical manifestations of scurvy is unclear.
The first two, having obvious involvements in the endocrine and
nervous systems, could well be causally related to various functional
derangements of scurvy; and as carnitine has an important role
in the transport of fatty acids into the mitochondria, where they
may be oxidized to provide energy, it has been suggested that
the carnitine involvement could account for the lassitude and
fatigue that have been invariably noted as an early feature of
scurvy (Hughes 1981a).
such involvements require an availability of ascorbic acid greater
than that required to prevent the emergence of "classical"
scurvy and there is some evidence that this is so, at least
in the case of carnitine biosynthesis then a revision of
the currently accepted Recommended Dietary Allowance/Reference
Value would be called for (Hughes 1981a). The current recommended
daily intake of vitamin C (60 mg in the United States and recently
raised from 30 to 40 in the United Kingdom) is, after all, the
amount estimated to prevent the emergence of the classic ("collagen")
features of scurvy and in the United Kingdom, it is based,
essentially, on a single experiment completed almost half a century
ago on a nonrepresentative population sample.
C is a heat-labile, water-soluble, and readily oxidizable molecule,
and its distribution among foodstuffs and the losses resulting
from processing and food preparation have been well documented.
Studying the losses induced in the vitamin C content of various
foodstuffs by simple culinary procedures must be one of the commonest
and oft-repeated projects in basic college and university courses,
and the amount of unpublished data resulting from these studies
must be immense.
mean daily intake of vitamin C in the United Kingdom (based on
noncooked purchases) is about 60 mg daily with potatoes, citrus
fruits, and cabbage accounting for 20, 12, and 6 percent, respectively,
of the intake. The losses resulting from cooking are substantial,
and these are further increased if the cooked food is allowed
to stand around before being eaten. Nevertheless, because of the
comparatively widespread distribution of the vitamin in plant
foodstuffs, and the role of technology in increasing the availability
of uncooked plant and vegetable material during the whole year,
very few persons today appear to suffer from clinically defined
hypovitaminosis C; consequently, frank scurvy is an almost unknown
recent survey of vitamin C intakes in European countries revealed
an interesting, and almost providential, reciprocity between the
consumption of two important sources of vitamin C. Of 27 countries
studied, Iceland, Switzerland, and France had the lowest annual
consumption of cabbage (less than 5 kg per capita) but a high
consumption of citrus fruit (over 20 kg); Romania, Poland, and
the former Soviet Union, in contrast, had the lowest consumption
of citrus fruit (less than 4 kg) but the highest consumption of
cabbage (more than 30 kg) (Kohlmeier and Dortschy 1991). Only
where a person, for ideological, economic, or supposed "health"
reasons subsists on a diet devoid of fruit and vegetables (such
as one based on nuts, grain, and/or cooked meat/fish) is scurvy
likely to emerge.
foliage of many flowering plants has an unexpectedly high concentration
of vitamin C, with concentrations of up to 1 percent wet weight
being attained in some members of the Primulaceae family. The
mean concentration for 213 species examined (162 mg per 100 g)
was some three times that of those culinary vegetables usually
regarded as good sources of the vitamin; and the mean value for
the leaves of 41 woody shrubs and trees examined was 293 mg per
100 g significantly higher than black currants, which are
usually cited as the dietary source par excellence of vitamin
C (Jones and Hughes 1983, 1984; see also Table IV.A.3.1).
historically important "antiscorbutic herbs" are among
the poorest sources of vitamin C (Hughes 1990). William Perry,
who stowed boxes of mustard greens and cress on board his ship
in an attempt to fend off scurvy during his Arctic expedition
of 1818 (Lloyd and Coulter 1963: 108), would have done better
to adorn his stateroom with primrose plants, a single leaf of
which, chewed in the mouth daily, would have sufficed to offer
complete protection. The exact reason, if any, for these high
(and often disparate) concentrations of ascorbic acid in angiosperms
is not known; nor is the role of ascorbic acid in plant biochemistry
understood. It has been suggested that there is a positive correlation
between the concentration of ascorbic acid in plants and corresponding
concentrations of phenolic compounds, but the extent to which
this reflects a biochemical relationship is a matter of conjecture
(E. C. Bate-Smith, personal communication).
practice of ingesting daily doses of vitamin C grossly in excess
of the amount believed to protect against scurvy and even in excess
of the amount known to produce tissue saturation is one of the
more controversial aspects of current nutritional thought. The
arguments for vitamin C "megatherapy" were initially
outlined in the United States by Irwin Stone and later elaborated
by Linus Pauling, winner of two Nobel Prizes (Hughes 1981b: 4753).
Stone disputed the adequacy of current recommended daily intakes,
basing his case primarily on the rate of biosynthesis of the vitamin
by animals producing their own supply and on G. H. Bournes
estimate that the natural diet of the gorilla provides it with
a daily intake of some 4.5 g ascorbic acid (Bourne 1949). His
arguments for daily intakes of grams rather than milligrams were
enthusiastically embraced and extended by Pauling.
interwoven with the megatherapy theory is the claim that vitamin
C has a number of extra-antiscorbutic functions (protection against
infection and, particularly, the common cold, detoxication, cerebral
function, lipid metabolism, longevity, and so forth) that might
require significantly raised amounts of the vitamin (Hughes 1981b:
1434). For example, E. Ginter has for many years carefully
presented the thesis that vitamin C plays a part in lipid metabolism,
particularly by enhancing the conversion of cholesterol to bile
salts, and that it would, therefore, have a hypocholesterogenic
function (Ginter and Bobek 1981).
date, however, there is little evidence that these putative relationships
are reflected by a specific and increased demand for vitamin C.
And as indicated earlier, some of these supposed secondary roles
have now been subsumed in enzymatic terms by the advances of reductionist
biochemistry. Secondary (or extra-antiscorbutic) roles for vitamin
C could, conceivably, require intakes greater than those necessary
for the prevention of classical scurvy, but such increased requirements
would, in biochemical terms, scarcely justify the massive intakes
recommended by the megatherapists.
from the lack of satisfactory evidence, there are other arguments
against vitamin C megatherapy (Jukes 1974; Hughes 1981b: 4753).
Adverse reactions elicited by massive doses of vitamin C and the
possibly toxic influence of its breakdown products could well
disadvantage the body. Moreover, the ingestion of large amounts
of ascorbic acid is a self-defeating exercise as the absorption
of large doses is a relatively inefficient process, with less
than one-half of a 1 g megadose being absorbed from the gastrointestinal
tract and only one-fourth of a 5 g dose (Davies et al. 1984; "Experimental
Scurvy" 1986). And, in any case, it is generally accepted
that tissue saturation in humans may be satisfactorily attained
by a daily intake of 100 to 150 mg or even less. The faith of
the megatherapists would have appeared to blind them to the normal
canons of scientific assessment.
the mid-1970s, Pauling espoused perhaps the most controversial
of all his vitamin C beliefs. In collaboration with a Scottish
surgeon, Ewan Cameron, he began to write extensively on the supposed
antitumor activity of vitamin C; more specifically, Cameron and
Pauling published the results of a clinical trial in which it
was claimed that a megadose (10 g daily) of vitamin C quadrupled
the survival time of terminally ill cancer patients (Cameron and
Pauling 1976). The methodology of this trial was widely criticized,
and a carefully controlled attempt to repeat it at the Mayo Clinic
in the United States failed to confirm the CameronPauling
claims. For the next 15 years, and in the face of growing reluctance
on the part of the scientific press to publish his papers, Pauling
continued to present his arguments for the efficacy of vitamin
C in the treatment of cancer. An account of this drawn-out battle
between Pauling and the American scientific establishment has
recently appeared (Richards 1991).
more general and theoretical terms, it has been suggested that
the antioxidant and free-radical scavenger roles of vitamin C
support its possible function in the prevention (as contrasted
with the cure) of cancer. G. Block has assessed some 90 studies
of cancer and vitamin C/fruit intake relationships and has concluded
that there is evidence that in the majority of cancers vitamin
C may have a significant prophylactic role (Block 1991). In this
respect, the possible relationship between vitamin C and nitrosamine-induced
cancers has attracted some attention.
has been speculated that endogenously produced N-nitroso compounds
may be important initiators of human cancers. Significant in this
respect is the formation of N-nitrosamines and related compounds.
Nitrosamines may be formed when nitrate, a suitable "nitrosable"
amine, and bacteria coexist as in the gastrointestinal
tract. Nitrate (the main dietary sources of which are fish and
root vegetables) is converted by bacterial action to nitrite,
which then reacts with amines to produce carcinogenic nitrosamines.
Some foods, particularly cured meat products, contain nitrosamines
formed during processing.
is evidence that vitamin C may prevent the formation of carcinogenic
nitrosamines from nitrate and may even reduce the carcinogenicity
of preformed nitrosamines (Hughes 1981b: 279; MAFF 1987).
It has been suggested, for example, that a reduction in nitrosamine
formation, attributable to citrus fruit vitamin C, may be a contributory
factor in determining the comparatively low incidence of large
bowel cancer in the "citrus belt" of the United States
(Lyko and Hartmann 1980). Sodium nitrite is used in the large-scale
preparation of cured meats, bacon, and sausages (primarily to
prevent the activity of the highly toxic Clostridium botulinum),
and these products, consequently, contain a range of preformed
nitroso compounds. There may, therefore, be good scientific reasons
for regarding orange juice as a useful dietary accompaniment to
a fried breakfast!
C and Industry
tens of thousands of tons of vitamin C are produced synthetically
each year from glucose; the initial stages in conversion involve
reduction to sorbitol followed by bacterial oxidation to sorbose.
Much of this vitamin C finds its way into health-food stores for
sale to megatherapy enthusiasts as a putative dietary adjuvant.
A substantial proportion is used industrially as a "technological
aid"; some is used in meat-curing processes to promote pigment
conversion (in this application, it also has an adventitious and
unintended role in reducing the formation of volatile N-nitrosamines).
C is also widely employed as a permitted antioxidant (sometimes
as ascorbyl palmitate) to prevent the formation of rancidity in
stored fat products and the phenolic browning of commodities such
as dehydrated potatoes. It is used as a flour improver in the
Chorleywood Bread Process, where its oxidation product (dehydroascorbic
acid) modifies the availability of glutathione in dough development,
thereby shortening the period of fermentation.
use of vitamin C in these technological processes finds general
approval on the grounds that one is, after all, adding a beneficial
vitamin rather than some untried additive of unknown toxicity.
It should be pointed out, though, that little of this additive
vitamin C is recoverable from the marketed product, which will,
however, contain substantial amounts of vitamin C breakdown products
many of them unidentified and almost all of them of unknown
toxicity. Bread is vitamin Cfree despite the substantial
amounts that may have been added during the Chorleywood process.
It has been estimated that the average consumer may ingest up
to 200 mg a week of vitamin C breakdown products from additive
sources (Thomas and Hughes 1985).
vitamin C should have attracted so much attention in nutritional
circles orthodox and otherwise is difficult to understand.
Its almost limitless appeal to health enthusiasts and pseudonutritionists
is matched only by the time and attention devoted to it by academic
nutritionists. The annual global publication of some 2,000 papers
bearing on vitamin C implies an annual research expenditure of
some £40,000,000 (about 60 to 70 million U.S. dollars)
a not inconsiderable sum for studying a molecule whose nutritional
significance is, at the most, marginal. Vitamin C deficiency is
today a rare occurrence, and the evidence for extra-antiscorbutic
requirements in excess of the mean daily intake is slender. Perhaps
the biochemical versatility of the vitamin C molecule makes it
attractive to biochemists who feel that it deserves a much more
significant role than that of a somewhat prosaic involvement in
the biosynthesis of collagen.
are some questions that remain unanswered. For example, the apparent
negative correlation between blood and tissue concentrations of
vitamin C and age is puzzling. Many very elderly subjects
particularly if institutionalized have virtually no ascorbic
acid in their blood, a situation that would almost certainly be
associated with the emergence of clinical scurvy in a younger
age group. Yet these octogenarians and nonagenarians seem to be
in no way disadvantaged by the apparent absence of the vitamin.
Is there, then, a negative correlation between aging and dependency
upon vitamin C? Such a relationship, if true, would be a remarkably
fortuitous one as a substantial proportion of the institutionalized
elderly have intakes of vitamin C well below the recommended daily
amount. It is a somewhat sobering thought that in these days of
scientifically attuned dietetics the mean intake of vitamin C
by the institutionalized elderly in the United Kingdom is no greater
than it was in hospitals a century and a half ago (Jones, Hughes,
and Davies 1988).
the more rarefied atmosphere of academic biochemistry, however,
it is possible to point to real advances in our knowledge of vitamin
C over the past 40 years. Today, modern high-performance liquid
chromatographic techniques are replacing the classical indophenol
dye method for the determination of vitamin C, with an increase
in sensitivity and specificity. Our knowledge of possible biochemical
involvements of the vitamin has advanced substantially. Sadly,
however, one cannot point with equal certainty to any corresponding
expansion of our knowledge of the nutritional significance of
vitamin C beyond its role in the prevention of classical scurvy.
R. G., D. K. Baird, H. C. Carrington, et al. 1933. Synthesis of
d- and L-ascorbic acid and of analogous substances. Journal
of the Chemical Society 1: 141923.
M. J., and E. Kodicek. 1972. Biological hydroxylations and ascorbic
acid with special regard to collagen metabolism. Vitamins and
Hormones 30: 143.
T. K., and C. J. Schorah. 1981. Vitamin C in health and disease.
T. W., L. J. Harris, and S. N. Ray. 1933. Hexuronic (ascorbic)
acid as the antiscorbutic factor, and its chemical determination.
Nature 131: 2734.
E. C., R. Jenness, and K. M. Ayaz. 1976. Inability of bats to
synthesize L-ascorbic acid. Nature 260: 6268.
G. 1991. Epidemiologic evidence regarding vitamin C and cancer.
American Journal of Clinical Nutrition 54: 1310S14S.
G. H. 1949. Vitamin C and immunity. British Journal of Nutrition
G. 1840. Scurvy. In The library of medicine. Practical medicine,
Vol. 5, ed. A. Tweedie, 5895. London.
Disorders resulting from defective nutriment. London Medical
Gazette 2: 6326, 71216, 7439, 90615.
E., and L. Pauling. 1976. Supplemental ascorbic acid in the supportive
treatment of cancer: Prolongation of survival time in terminal
human cancer. Proceedings of the National Academy of Science
K. J. 1986. The history of scurvy and vitamin C. Cambridge
and New York.
K. C. 1977. The germ theory, beriberi, and the deficiency theory
of disease. Medical History 21: 11936.
I. B. 1973. Evolution and biosynthesis of ascorbic acid. Science
H., and M. Hume. 1917. The distribution among foodstuffs . . .
of the substances required for the prevention of (a) beriberi
and (b) scurvy. Transactions of the Royal Society for Tropical
Medicine and Hygiene 10: 14186.
H. E. F., J. E. W. Davies, R. E. Hughes, and Eleri Jones. 1984.
Studies on the absorption of L-xylo ascorbic acid (vitamin C)
in young and elderly subjects. Human Nutrition: Clinical Nutrition
J. C. 1919. Note on the role of the anti-scorbutic factor in nutrition.
Biochemical Journal 13: 7788.
B. A., and R. E. Mains. 1991. The role of ascorbate in the biosynthesis
of neuroendocrine peptides. American Journal of Clinical Nutrition
S., and S. Seifter. 1986. The biochemical functions of ascorbic
acid. Annual Review of Nutrition 6: 365406.
scurvy in a young man. 1986. Nutrition Reviews 44: 135.
P. J., and U. M. Kent. 1991. Cytochrome b561, ascorbic acid, and
transmembrane electron transfer. American Journal of Clinical
Nutrition 54: 1173S8S.
E. 1980. What is truly the maximum body pool of ascorbic acid
in man? American Journal of Clinical Nutrition 33: 5389.
E., and P. Bobek. 1981. The influence of vitamin C on lipid metabolism.
In Vitamin C (ascorbic acid), ed. J. N. Counsell and D.
H. Hornig. London.
A., and S. S. Zilva. 1918. The antiscorbutic factor in lemon juice.
Biochemical Journal 12: 25969.
L. J. 1937. Vitamins in theory and practice. New York and
Chairmans summing-up. Proceedings of the Nutrition Society
W. N., E. L. Hirst, and S. S. Zilva. 1934. Physiological activity
of synthetic ascorbic acid. Journal of the Chemical Society
E. L. 1953. The chemistry of vitamin C. In Linds treatise
on scurvy, ed. C. P. Stewart and D. Guthrie, 41324.
A., and T. Fröhlich. 1907. Experimental studies relating
to ship beri-beri and scurvy. II. On the etiology of scurvy. Journal
of Hygiene 7: 63471.
F. G. 1912. Feeding experiments illustrating the importance of
accessory factors in normal dietaries. Journal of Physiology
R. E. 1973. George Budd (18081882) and nutritional deficiency
diseases. Medical History 17: 12735.
Recommended daily amounts and biochemical roles the vitamin
C, carnitine, fatigue relationship. In Vitamin C (ascorbic
acid), ed. J. N. Counsell and D. H. Hornig. London.
Vitamin C: Some current problems. London.
From ignose to hexuronic acid to vitamin C. Trends in Biochemical
Science 8: 1467.
The rise and fall of the "antiscorbutics": Some notes
on the traditional cures for "land scurvy." Medical
History 34: 5264.
C. S. 1991. Complement component Clq unaltered by ascorbate supplementation
in healthy men and women. Nutritional Biochemistry 2: 499501.
E., and R. E. Hughes. 1983. Foliar ascorbic acid in some angiosperms.
Phytochemistry 22: 24939.
A note on the ascorbic acid content of some trees and woody shrubs.
Phytochemistry 23: 23667.
E., R. E. Hughes, and H. E. F. Davies. 1988. Intake of vitamin
C and other nutrients by elderly patients receiving a hospital
diet. Journal of Human Nutrition and Dietetics 1: 34753.
T. H. 1974. Are recommended and daily allowances for vitamin C
adequate? Proceedings of the National Academy of Science
The identification of vitamin C, an historical summary. Journal
of Nutrition 118: 12903.
A. 1981. Vitamin C mans requirements. In Vitamin
C (ascorbic acid), ed. J. N. Counsell and D. H. Hornig. London.
C. G. 1953. The discovery and chemistry of vitamin C. Proceedings
of the Nutrition Society 12: 21927.
L., and R. Dortschy. 1991. Diet and disease in East and West Germany.
Proceedings of the Nutrition Society 50: 71927.
M., and K. Morita. 1985. Ascorbic acid in endocrine systems. Vitamins
and Hormones 42: 164.
H. C., and J. L. S. Coulter. 1963. Medicine and the navy, 12001900,
Vol. 4. Edinburgh and London.
H. C., and J. X. Hartmann. 1980. Ascorbate, cyclic nucleotides,
citrus and a model for preventing large bowel cancer. Journal
of Theoretical Biology 83: 67586.
L. W. 1967. Biogenesis of L-ascorbic acid in plants and animals.
In The Vitamins, Vol. 1, ed. W. H. Sebrell and R. S. Harris,
36983. New York and London.
of Agriculture, Fisheries, and Food (MAFF). 1987. Nitrate,
nitrite and N-nitroso compounds in food. London.
R. W. 1987. Free radical: Albert Szent-Györgyi and the
battle over vitamin C. New York.
L. 1976. Vitamin C, the common cold and the flu. San Francisco.
B. 1991. Ascorbate requirement for hydroxylation and secretion
of procollagen: Relationship to inhibition of collagen synthesis
in scurvy. American Journal of Clinical Nutrition 54: 1113S27S.
C. J. 1991. Ascorbic acid and carnitine biosynthesis. American
Journal of Clinical Nutrition 54: 1147S52S.
T., A. Grussner, and R. Oppenheimer. 1933. Synthesis of d- and
L-ascorbic acid (vitamin C). Nature 132: 280.
E. 1991. Vitamin C and cancer. London.
P., and S. Uderfriend. 1978. Studies on ascorbic acid related
to the genetic basis of scurvy. Vitamins and Hormones 36:
J. L., and A. Szent-Györgyi. 1932. Hexuronic acid as the
antiscorbutic factor. Nature 129: 576.
A. 1928. Observations on the function of the peroxidase systems. . . .
Biochemical Journal 22: 13871409.
Lost in the twentieth century. Annual Review of Biochemistry
M., and R. E. Hughes. 1985. Evaluation of threonic acid toxicity
in small animals. Food Chemistry 17: 7983.
W. R., and P. G. Holt. 1978. Vitamin C and immunity: An assessment
of the evidence. Clinical and Experimental Immunology 32:
C regulation of cartilage modification. Nutritional Reviews
A., and C. G. King. 1932. The isolation and identification of
vitamin C. Journal of Biological Chemistry 97: 32531.
L. G. 1975. The clinical definition of scurvy and the discovery
of vitamin C. Journal of the History of Medicine 30: 4060.
S. S. 1932. Hexuronic acid as the antiscorbutic factor. Nature