Ascorbic Acid: Physiology and Health Effects
ZAM Daud, A Ismail, and B Sarmadi, Universiti Putra Malaysia, Serdang, Malaysia
ã 2016 Elsevier Ltd. All rights reserved.
Introduction
Vitamin C also known as L-ascorbic acid is an essential dietary
nutrient required for numerous biological processes of the
body. Human and several other animal species including
primates and guinea pig are unable to synthesize it due to a
deficiency of L-gulonolactone oxidase, a terminal enzyme in
the biosynthetic pathway of ascorbic acid, because of mutation
in the gene encoding for the enzyme. Therefore, vitamin C
must be solely obtained from the diet to maintain a normal
metabolic functioning of the body. Many fruits and vegetables
including citrus fruits, guava, tomatoes, red and green peppers,
kiwifruit, and broccoli are the predominant sources of vitamin
C supplying more than 80% of the daily needs. Thus, con-
sumption of adequate serving of fresh fruits and vegetables
daily will ensure vitamin C adequacy. Diet insufficient in vita-
min C (defined as plasma vitamin C levels of <11 mmol l
1)
leads to a lethal condition known as scurvy, characterized by
gingival changes, pain in the extremities, and hemorrhagic
manifestation leading to death. On the other hand, marginal
and suboptimal plasma and vitamin C levels have been asso-
ciated with increased risk of death from all cause of mortality
and cancer.
Over the years, vitamin C has received a greater scrutiny
beyond its antioxidant function. Research trends in vitamin C
have moved forward from preventing deficiency to investigat-
ing its therapeutic value. In conjunction with this, the recom-
mendation for vitamin C intake is being reviewed in light of
new evidences pertaining to the role of vitamin C in health and
diseases. In fact, this issue remains a debatable topic, as there is
no common ground on the amount needed to maintain opti-
mum health. Vitamin C has been controversially used to pre-
vent or delay the occurrence of chronic diseases and to treat
certain illnesses. The aim of this article is to discuss briefly the
established aspects of vitamin C physiology and its relation to
health and disease conditions. Current evidences on the ther-
apeutic role of vitamin C in several chronic illnesses including
cardiovascular disease (CVD), cancer, and respiratory illnesses
will be discussed.
Physiology of Vitamin C
Ascorbic acid is present in all parts of the body at varying
concentration in the plasma, bone cells, and cellular immune
system. Body stores of vitamin C can be affected by dietary
intake, excretion rate in renal tubule, fecal losses, and meta-
bolic losses. Most of the physiological functions of vitamin C
are related to its oxido-reduction properties. It acts as a cofactor
for hydroxylases and monooxygenase enzymes involved in the
synthesis of collagen, carnitine, and neurotransmitters. Ascor-
bic acid maintains the metal ions’ active center in reduced form
to keep hydroxylase and oxygenase in their optimal activity
266 Encyclopedia of Food and Health
and thereby enhance hydroxylation functions. These will be
described briefly in the following subsections.
Absorption, Metabolism, Storage, and Excretion
Upon ingestion of vitamin C, the intestinal absorption that
takes place is based on two known pathways (Figure 1): (1) the
facilitated diffusion mediated by the facilitative glucose trans-
porter (GLUT) and (2) a saturable-substrate transport mecha-
nism via ascorbate-specific transporter (sodium vitamin C
transporter (SVCT)). Oral vitamin C is absorbed for approxi-
mately 70–90% at moderate intake (30–180 mg day
1), but
absorption rate falls below 50% at intake above 1000 mg
day
1. Pharmacokinetics studies revealed that consumption
of at least 200 mg day
1 of vitamin C in healthy young adults
leads to plasma concentration of more than 50 mM, which is a
nearly complete oral bioavailability, indicated by leukocyte
saturation and minimum urinary excretion. This suggests that
ingestion of vitamin C orally produces plasma concentrations
that are tightly controlled.
Absorbed vitamin C is transported in the plasma as free
anion ascorbate and is distributed to all tissues. At cell levels,
particularly in the osteoblast, muscle, and retinal cells, an
oxidized form of vitamin C known as dehydroascorbic acid
(DHA) is taken up by GLUT and then reduced internally to
ascorbic acid. Because DHA shares the same transporter as
glucose, this leads to competitive inhibition particularly during
altered serum glucose levels such as hyperglycemia secondary
to diabetes. On the other hand, active transportation of ascor-
bate via SVCT is subjected to substrate feedback inhibition
indicating a regulatory role in maintaining ascorbate concen-
tration in the cells.
In terms of body store, a total body content of vitamin C in
healthy adults ranges from 300 mg to 2 g with higher concen-
trations maintained in the leukocytes, eyes, adrenal glands,
pituitary gland, and brain. Excessive vitamin C intake that is
not metabolized is excreted mainly in the urine, although
some can also be found in the feces. Maximum metabolic
losses of vitamin C in healthy nonsmoking men range from
40 to 50 mg day
1. Smokers are found to have 50% higher
metabolic losses than nonsmokers.
In human, the main route of removal of ascorbic acid is
through urinary excretion. For this purpose, ascorbic acid is
oxidized to dehydroascorbic acid, which is subsequently
hydrolyzed to diketogulonic acid. The catabolism of ascorbic
acid is completed by decomposition of diketogulonic acid to
various compounds such as oxalic and threonic acids
(Figure 2).
Safety Levels and Toxicity
Generally, vitamin C is relatively safe even at doses up to
several grams per day. This is due to the fact that the
http://dx.doi.org/10.1016/B978-0-12-384947-2.00045-3

Plasma GLUT
SVCT2
Figure 1 Vitamin C absorption across the intestinal epithelium. GLUT, glucose transporter; SVCT, sodium vitamin C transporter; AA, ascorbic acid;
DHA, dehydroascorbic acid.
2H+
Ascorbic acid Dehydroascorbic
acid
Figure 2 Catabolic pathway of vitamin C.
physiological concentration of vitamin C in the body is tightly
regulated by alteration in the intestinal absorption, kidney
excretion, and cellular transport. The upper tolerable level,
the highest level of daily nutrient intake at which it is likely
to pose no risk of adverse effects for most individuals, of
vitamin C for adults is set at 2 g day
1. Vitamin C intake at
dose beyond 3 g day
1 is associated with gastrointestinal dis-
turbance due to the unabsorbed ascorbate. However, partici-
pants that were administered intravenous vitamin C up to
100 g per infusion within a few hours in a pharmacokinetics
study did not report any adverse effects, demonstrating the
safety of this vitamin at megadose.
Nevertheless, high doses of vitamin C are contraindicated
in special population including chronic kidney disease patients
and hyperoxaluria due to inability to excrete excessive oxalate
from metabolic conversion of vitamin C. Meanwhile, in
patients with glucose-6-phosphate dehydrogenase deficiency,
high doses of vitamin C could induce acute hemolysis.
Ascorbic Acid: Physiology and Health Effects 267
Diffusion
DHA
AA
GLUT
SVCT
Intestinal Epithelium
H2O
Diketogulonic
acid
Oxalic acid,
Threonic acid,
Other metabolites
Urinary
excretion
Moreover, high doses of vitamin C could hamper copper
absorption and thus inhibit copper-containing superoxide dis-
mutase, an important enzyme in antioxidant defense. On the
other hand, very high doses of vitamin C could enhance intes-
tinal iron absorption to a dangerous level among individuals
with hereditary diseases such as hemochromatosis and thalas-
semia. It has been shown in some studies that excessive vita-
min C intake (>1 g day
1) may induce severe urine
acidification, leading to impaired excretion of weak acids and
bases, resulting in deposition of cystinate and urate in the
urinary tract and formation of kidney stones.
Mechanism of Action of Vitamin C
Vitamin C is a water-soluble vitamin that is mostly known for
its antioxidant function, which is defined as “any substance
that, when present at low concentration compared to those of
an oxidizable substrate, significantly delay or prevent
268 Ascorbic Acid: Physiology and Health Effects
oxidation of that substrate.” This is attributed to two major
properties of vitamin C as an ideal antioxidant:
(1) The ability to readily scavenge free radicals including reac-
tive oxygen species and nitrogen species such as superox-
ide, hydroperoxyl radicals and nitroxide radicals, single
oxygen, nitrogen dioxide, and hypochlorite species, thus
protecting substrates (e.g., protein, lipids, carbohydrates,
and nucleic acid) from oxidative damage
(2) Stability and low reactivity of ascorbyl radical formed from
these scavenging activities
When ascorbate quenches free radicals by donating electrons,
ascorbyl radical with low reactivity is generated. Ascorbyl rad-
ical reacts with another radical to form DHA. The ascorbyl
radical and DHA can be returned to reduced form (ascorbate)
by electron donors like glutathione and NADPH.
Vitamin C acts as an electron donor to several enzymes –
some participate in collagen hydroxylation and some other in
carnitine and catecholamine biosynthesis. Vitamin C acts as
cosubstrate to reduce the active center of metal ion of various
mono- and dioxygenases and maintain them in a reduced
state. Moreover, vitamin C has also been shown to spare
other intercellular antioxidants such as glutathione by main-
taining them at reduced state. Vitamin C can also regenerate a-
tocopherol from the a-tocopheroxyl radical; thereby, it acts as
an important co-antioxidant in the absence of which vitamin E
can act as a pro-oxidant. Similarly, vitamin C could also regen-
erate one-electron oxidation products of various antioxidants
including urate, glutathione, and b-carotene (Figure 3). How-
ever, in vitro experiments demonstrate that vitamin C could
also act as pro-oxidant. Its pro-oxidant activity is agreed to be
dependent on the concentrations used and on the presence of
transition metal ions like copper and iron. It has been reported
that high doses of exogenous iron (200 mg) and ascorbic acid
R• RH
Vitamin E
T Cycle T•
Vitamin C AA
Cycle
DHA
RH
R• GSH
GSSG
GSSG
Figure 3 Role of vitamin C in neutralizing free radicals and its
interrelationship with other antioxidants. Abbreviations: R•, free radicals;
T, tocopherol (vitamin E); T•, tocopheroxyl radicals; AA, ascorbic acid;
DHA, dehydroascorbic acid; GSH, glutathione; GSSG, glutathione
disulfide (oxidized glutathione).
(75 mg) release iron from iron-binding proteins and promote
in vitro serum lipid peroxidation of guinea pigs. Ascorbate
reduces these metals, which may react with H2O2 and subse-
quently •OH production; this reaction is known as Fenton
chemistry. Reduced metals may also react with lipid hydroper-
oxides that results in production of lipid alkoxyl radicals;
subsequently, these lipid alkoxyl radicals can initiate and pro-
mote lipid peroxidation. However, such effect is preventable in
the presence of sufficient antioxidants (like glutathione). In
addition, since metal ions have the capacity to transfer one
electron, in biological systems, they bind to proteins; thus,
these metal ions become less effective than free-radical cata-
lysts. In line with this, no convincing data are available to
demonstrate that this actually occurs in human.
Despite a wealth of knowledge on the antioxidant function
of vitamin C from cultured cells and experimental animals,
data in human are relatively scarce. This is partly attributed to
the fact that human studies may be cofounded by various
factors including the bioavailability, presence of illnesses,
genetic variations especially with regard to vitamin C trans-
porter, erroneous in dietary estimation, and lack of specific
biomarkers. The most conclusive evidences to demonstrate
antioxidant effects of vitamin C may be coming from lipids,
DNA, and protein oxidation biomarkers. Several lines of
evidence indicate that supplementation with vitamin C
significantly reduced lipid peroxidation biomarkers (e.g.,
F2-isoprostanes) and DNA damage (e.g., lymphocyte DNA
damage – comet assay). Nevertheless, this effect is dependent
on baseline vitamin C concentration. Supplementation with
vitamin C cannot further reduce the oxidative damage if tissues
levels of vitamin C are already saturated.
Dietary Intake and Recommendation
Various factors have been identified to affect vitamin C require-
ment. These include bioavailability, nutrient-to-nutrient
interactions, and gender. There are various dietary guidelines
available from diverse professional bodies pertaining to vita-
min C intake recommendation. One of the commonly referred
to is dietary references intake that was developed and main-
tained by the Institute of Medicine of the National Academy
(see ‘Further Reading’ section). Based on this guideline, adult
male requires 90 mg day
1 of vitamin C, while nonpregnant
and lactating women require 75 mg day
1. Deutschland-
Austria-Confoederatio Helvetica (D-A-CH, 2013) and the
European Food Safety Authority (EFSA, 2013) recommend
higher intake (D-A-CH: 100 mg day
1 for adults regardless of
gender; EFSA: 110 mg day
1 for men and 95 mg day
1 for
women >18 years old) to outweigh the benefit of higher intake
on the reduction in the risk of chronic diseases. Generally,
vitamin C requirement is increased in special population
including pregnant and lactating women as well as smokers
when compared to their age group counterpart (Table 1). This
is to reflect the different physiological requirements in these
groups. In pregnant women, higher requirement is needed to
account for expansion of blood volume and active transfer to
the fetus, while for lactating women, to account for vitamin C
transfer to breast milk. For heavy smokers (i.e., smoking more
than 20 cigarettes per day), higher intake is needed to account
 Ascorbic Acid: Physiology and Health Effects 269

Table 1 Dietary reference intake for vitamin C health and disease with its potential mechanism of action is
summarized in Table 2.
Gender

1
Age group Male (mg day ) Female (mg day
1) Collagen Biosynthesis and Wound Healing
a
0–6 months 40 40 Collagen is the main structural protein in various connective
7–12 monthsa 50 50 tissues, including those found in tendons, ligaments, skin,
1–3 years 15 15 cornea, cartilage, and blood vessels. Different types of
4–8 years 25 25 collagens that are the main components of the extracellular
9–13 years 45 45 matrix comprise 30% of total protein mass. The main struc-
14–18 years 75 65
tural protein of the interstitial extracellular matrix is type I
19 years 90 75
Pregnancy/lactation
collagen, whereas type IV collagen is found predominantly in
14–18 years – 80/115 the basement membrane. In the extracellular matrix, collagens
19 years – 85/120 behave as chief constituents of the physical barrier against
Smokers Additional 35 mg day
1 invasion of cancer cells. In human skin fibroblasts, ascorbate
has been suggested to stimulate the generation of types I and III
a
For age group of 0–12 months, the DRI was calculated based on adequate intake (AI), collagen. Vitamin C plays an essential role during collagen
while the rest of the age group was based on recommended dietary allowance (RDA).
biosynthesis, acting as a specific electron donor for proline
Source: Institute of Medicine. (2000). Vitamin C. DRI Dietary Reference Intakes for
hydroxylase, lysine hydroxylase, and procollagen-proline
Vitamin C, Vitamin E, Selenium and Carotenoids, pp. 95–185. Washington, DC:
National Academy Press.
2-oxoglutarate 3-dioxygenase, all of which take part in the
posttranslational hydroxylation of peptide-bound proline
and lysine residues of collagen, imperative for stable collagen
helices formation. Procollagen is a precursor molecule to the
protein collagen that contains unusual amino acid sequence:
for reduced absorption and increased daily turnover pertaining hydroxyproline and hydroxylysine, converted from proline
to higher oxidative stress in this population. and lysine after the procollagen molecule has been synthe-
Vitamin C intake in various nutrition surveys in the United sized. The enzyme involved in this process of hydroxylation,
States and Europe indicated adequacy levels. For example, prolyl hydroxylase, requires ascorbic acid, iron, and a-
based on the National Health and Nutrition Examination Sur- ketoglutarate to catalyze the formation of hydroxyproline.
vey of the United States (NHANES 2009–10), average levels of Throughout the process of hydroxylation, the enzyme-bound
vitamin C intake among males and females over 20 years old iron is oxidized (Fe3þ) and then ascorbic acid reduces the iron
are 95.6 and 82.7 mg day
1, respectively. Similarly, average to ferrous state (Fe2þ), thus reactivating the enzyme. In a
vitamin C intake (excluding supplements) among adult comparable reaction, ascorbic acid acts as a cofactor for a
males and females in European countries ranges from 69 to copper-dependent lysyl hydroxylase that contributes in the
139 mg day
1 and 65 to 138 mg day
1, respectively. However, hydroxylation of lysine to hydroxylysine. Therefore, deficiency
vitamin C intake in some Asian countries may not reach the in vitamin C results in impaired collagen biosynthesis.
adequacy levels. This has been demonstrated in a publication Wound healing process also heavily relies on dietary suffi-
from India that showed that the available supply of vitamin C ciency, especially of vitamin C. Ascorbic acid plays an impor-
is 43 mg per capita per day, which ranges from 27 to 66 mg tant role in all phases of wound healing. During ‘inflammatory
day
1 depending on locality. This is supported by the fact that phase,’ (i.e., the body’s natural responses to injury), vitamin C
plasma levels of vitamin C among native South Asian popula- is required for neutrophil apoptosis and clearance as well as to
tions are relatively much lower when compared to South Asian neutralize free radical formed as part of scavenging process. As
living abroad. It is to acknowledge that differences in method- the wound progresses to ‘proliferation phase’ (i.e., the wound
ologies may have an impact on the accuracy of this country-to- is rebuilt with new granulation tissues comprising collagen and
country comparison. extracellular matrix), vitamin C is needed as a cofactor for
synthesis of collagen tissues. While during ‘maturation phase’
(i.e., remodeling of collagen from type III to I, occurring after
the wound has closed), vitamin C is needed to maintain integ-
Role of Vitamin C in Human Health and Diseases rity of collagen production and scar formation. Such role has
been demonstrated in a randomized, double-blind, placebo-
There is substantial amount of literature from in vitro animal controlled trial involving 20 trauma patients with disorders in
model and human studies that investigate the role of vitamin C wound healing. Supplementation with antioxidant (including
in health and chronic diseases. For the purpose of this article, vitamin C) has been shown to reduce time to wound closure.
only studies involving human will be included for discussion. Even though the exact role of vitamin C cannot be ruled out
This is based on the fact that ascorbic acid is not an essential due to the mixture with some other antioxidants in the sup-
nutrient for most animals – thus, studying genetically variant plementation, vitamin C may act synergistically with the other
strain incapable of synthesizing ascorbic acid may not fully antioxidant nutrients to promote wound healing. In addition
recapitulate vitamin C transport functions and imitating dis- to collagen, ascorbic acid plays a role in the synthesis of other
ease condition associated with vitamin C depletion and sup- connective tissue constituents, like fibronectin, elastin, proteo-
plementation as in human. The role of vitamin C in human glycans, bone matrix, and elastin-associated fibrillin.
270 Ascorbic Acid: Physiology and Health Effects

Table 2 Role of vitamin C in health and diseases and its potential mechanism of action

Health and disease

condition Vitamin C role Possible mechanism of action

Cancer Pro-oxidant (high
dosage) for adjunct
cancer treatment
Antioxidant for cancer
prevention
(anticarcinogenic
effect)
Cardiovascular Antioxidant/anti-
diseases inflammatory
properties
Antihypertensive effect
Lipid-lowering effect
Cataract and ocular Antioxidant
diseases
Collagen biosynthesis Acts as electron donor
and wound healing to specific enzymes
of collagen
biosynthesis
Iron absorption Potent enhancer/
physiological role
Osteoporosis and Acts as electron donor
fractures to specific enzymes
of collagen
biosynthesis
Sepsis Antioxidant
AA needs to be administered intravenously in order to achieve effective concentration. High
dosage of vitamin C has been shown to
– create pro-oxidant environment and accelerate irreversible damage of the tumor cells,
– stimulate apoptotic pathway of the tumor cells,
– result in intermediate formation of H2O2 via ascorbate radicals, which in turn causes breaks in
DNA and mitochondria
– prevent cancer spread by increasing collagen synthesis, inhibiting hyaluronidase, increasing
extracellular matrix, and walling within the tumor cells
Normal to high physiological levels of plasma AA to neutralize mutagenic free radicals, reduce
oxidative stress, and prevent DNA damage
AA reduced oxidizability of LDL. LDL oxidation is one of the key steps in atherosclerosis. AA
decreases adherence of monocytes to endothelium, inhibits proinflammatory cytokines, and
improves production of the endothelium-dependent nitric oxide
AA enhances production of nitric oxide, a potent vasodilator, by increasing intracellular
concentration of tetrahydrobiopterin, a cofactor for nitric oxide synthase. AA also improves
nitric oxide bioavailability
Suboptimal AA intake affects the activity of two cholesterol-regulating enzymes, namely, ACAT
and CETP. Increase in ACAT leads to higher LDL-C, while increase in CETP will result in lower
HDL-C. AA as an antioxidant may protect VLDL and promote its removal from plasma.
Moreover, AA may increase fatty acid utilization in hepatocytes by enhancing carnitine
synthesis. Taken together, increased VLDL removal and b-oxidation of fatty acids lead to
lower TAG
Lens is prone to opacification due to its high protein content. Maintaining adequate blood levels of
AA may reduce the risk of cortical, nuclear, and PSC cataract by providing protective effect
against oxidative stress-related etiology
AA is involved in the synthesis and cross-linkage of collagen and has impact on vascular integrity
and capillary bed strength
AA enhances intestinal absorption of nonheme iron by chelating/maintaining iron in reduced form.
AA may interact and reduce dietary inhibitors of iron including phytates
Collagen is an essential component of bone tissue. AA mediates osteoclastogenesis and
osteoblastogenesis. AA is also involved in bone collagen synthesis, by acting as a cofactor of
hydroxylation reaction within collagen fiber
Low levels of AA in critically ill patients are correlated with multiple organ failure. AA inhibits
apoptosis of endothelial cells, stimulates proliferation, and prevents the loss of barrier function
in sepsis condition

Note: AA, ascorbic acid; DNA, deoxyribonucleic acid; LDL, low density lipoprotein; VLDL, very low density lipoprotein; HDL, high density lipoprotein; TAG, triacylglyceride; ACAT,
acyl-CoA:cholesterol acyltransferase; CETP, cholesterylester transfer protein.

Synthesis of Neurotransmitter Vitamin C and Iron Absorption

Vitamin C is considered as a cosubstrate for copper-
containing dopamine-b-monooxygenase that converts neuro-
transmitter dopamine to norepinephrine by hydroxylation of
the dopamine side chain. In addition, ascorbic acid seems to
play a role in the hydroxylation of tryptophan that results in
the formation of serotonin in the brain. It has been shown
that glutamatergic and dopaminergic neuron activity has
been closely associated with changes in concentrations of
extracellular ascorbic acid in the brain. Results of animal
model and cell culture experiments suggested that ascorbic
acid plays an important role in the developing nervous sys-
tem, mainly for the growth and maturation of glial cells and
myelin.
Dietary vitamin C is known to enhance the intestinal absorp-
tion of nonheme iron by reducing intraluminal iron to a more
absorbable ferrous form. In addition, ascorbic acid can interact
with dietary inhibitors of iron absorption. Increase in iron
absorption with vitamin C may not cause adverse conse-
quences in healthy people. However, such enhancement of
iron absorption following consumption of high doses of vita-
min C can be of concern in case of iron overload, like
b-thalassemia and homozygous hemochromatosis, as vitamin
C can worsen iron overload and cause tissue damage.
In addition, while vitamin C increases iron absorption, it
can interact with iron and promote oxidative damage. This is
an additional concern about high supplemental intakes of

vitamin C that worsen iron overload and, subsequently, its
related pathology. Although high dose of iron intake may not
be an important factor in overloaded iron, iron-ascorbate cou-
ple has been reported to have a strong pro-oxidant nature, and
elevated levels of serum ascorbic acid have been shown to
restrain the ferroxidase activity of ceruloplasmin; as a result,
oxidative damage will be enhanced by amplified ferrous iron.
Cardiovascular Health
CVD including coronary heart disease (CHD), strokes,
cardiomyopathy, and other heart diseases remain to be the
leading causes of morbidity and mortality worldwide.
Although CVDs have been previously described as a ‘wealthy
nation disease,’ it is projected that by 2020, CVD will be the
major cause of death in most developing nations. Major risk
factors associated with CVD include increasing age, male gen-
der, dyslipidemia, hypertension, cigarette smoking, family his-
tory, obesity, and physical inactivity.
Oxidative damage of biomolecules such as lipids, DNA, and
proteins has become a working hypothesis that is widely
accepted in terms of its relation with initiation and development
of CVD. Several lines of evidence indicate that oxidation of low-
density lipoprotein (LDL) is the key factor contributing to
atherogenesis; thus, reduction in LDL oxidizability has become
one of the therapeutic targets of vitamin C. Moreover, vitamin C
contributes to cardiovascular health through its antioxidant prop-
erties, decreasing adherence of monocytes to the endothelium
and improving the production of endothelium-dependent nitric
oxide (NO). However, studies investigating the relationship
between vitamin C consumption and CVD show inconsistent
findings. Observational studies present a link between high vita-
min C intake and reduced risk of CVD, yet, randomized con-
trolled trials (RCT) on the effects of vitamin C supplementation
on endothelial function show conflicting results; some studies
indicated improvement in endothelial function, whereas others
presented no effect of vitamin C supplementation. Therefore, for
the ease of discussion, the evidence will be grouped into three
main components:
(1) Relationship and effects of vitamin C on overall mortality
and morbidity associated with cardiovascular health
(2) Effects of vitamin C on blood pressure
(3) Effects of vitamin C on plasma lipids
Relationship and effects of vitamin C on overall mortality
and morbidity associated with cardiovascular health
Several epidemiological studies have provided quite encourag-
ing results yet inconclusive regarding the relationship of vita-
min C intake and cardiovascular health. In a large European
prospective cohort study involving more than 20 000 partici-
pants, the relationship of plasma vitamin C and incidence of
heart failure for a mean follow-up of 12.8 years was assessed.
The results showed an inverse association between plasma
vitamin C and risk of heart failure after adjustment of
cofounders such as age, sex, smoking, systolic blood pressure,
and physical activity; every 20 mmol l
1 increase in plasma
vitamin C was associated with 9% relative reduction risk of
heart failure. This however may reflect overall intake of fruits
and vegetables; thus, specific constituents of the diet leading to
Ascorbic Acid: Physiology and Health Effects 271
reduced heart failure risk cannot be ruled out. A meta-analysis
of prospective studies to investigate the relationship of vitamin
C intake, plasma level, and risk of stroke was published. The
analysis included 12 prospective studies on vitamin C intake
and six prospective studies on circulating vitamin C (plasma/
serum levels). Results of this analysis suggest that both vitamin
C intake and circulating vitamin C are significantly inversely
associated with the risk of stroke.
From the clinical trial perspective, a 6-year antioxidant
supplementation (vitamin C and E) among 520 subjects with
the end point of common carotid artery intima-media thick-
ness. The supplementation was associated with significant
regression of atherosclerotic lesions in participants with low
baseline plasma vitamin C concentration. However, most data
from recent RCTs that evaluate role of vitamin C for prevention
of CHD or stroke are not as consistent as the population
studies and thus failed to produce convincing evidence to
advocate supplementation. Some of the limitations of RCTs
and the reason for disparate finding between epidemiological
studies have been discussed elsewhere. These include limita-
tion in dietary recalls to estimate vitamin C intake and the
failure of the intervention study to exclude subject who already
achieved saturation in circulating vitamin C as supplementa-
tion may not provide any additional benefit. Furthermore,
duration of supplementation and sample size are relatively
small in many RCTs.
Effects of vitamin C on blood pressure
Vitamin C has also been hypothesized to confer anti-
hypertensive effects. This is basically derived from the fact
that vitamin C enhanced endothelial functions via nitric
oxide production. Furthermore, epidemiological study has
also shown inverse correlation between plasma levels of vita-
min C and blood pressure. A meta-analysis of RCTs to examine
the effects of vitamin C supplementation on blood pressure
was conducted. A total of 29 trials were included in the analysis
with a median vitamin C supplementation of 500 mg day
1 for
a median duration of 8 weeks. It was found that vitamin C
modestly reduced blood pressure, with the pooled changes in
SBP and DBP being – 3.84 mm Hg and – 1.84 mm HD, respec-
tively. Nevertheless, this analysis was cofounded by heteroge-
neity of the data, relatively small sample size, and, more
importantly, variable control of antihypertensive medications
for each of the trials. In short, further evidence is needed to
outweigh the benefit of vitamin C supplementation on blood
pressure.
Effects of vitamin C on plasma lipids
In line with epidemiological evidence that vitamin C has an
inverse association with the development of atherosclerosis, it
has also been hypothesized that this effect could be mediated
by lipid-modifying effects. In a meta-analysis involving 13
RCTs, it was found that supplementation with at least
500 mg day
1 vitamin C among hypercholesterolemic subjects
led to significant reduction of LDL-C (
7.9 mg dl
1) and tri-
glycerides (
20.1 mg dl
1). Nevertheless, the magnitude of
changes is considered modest, thus the need for further evalu-
ation on the cost-effectiveness of the supplementation.
272 Ascorbic Acid: Physiology and Health Effects
Cancer
Carcinogenesis, or development of malignant cells, is a multi-
stage process. It is generally accepted that free radicals devel-
oped by carcinogens are implicated in the carcinogenesis
process. Vitamin C has received a great scrutiny in terms of its
role in the prevention and treatment of malignancy. However,
the effect of vitamin C on treatment and prevention of cancer is
very inconsistent despite a vast number of studies in this area.
In a recent meta-analysis based on the epidemiological studies
involving more than 8000 lung cancer cases, it was found that
vitamin C decreased risk for lung cancer in a dose–response
manner; lung cancer risk decreased by 7% for every 100 mg
day
1 increased in the intake of vitamin C. Similarly, another
meta-analysis of cohort studies that investigated the relation-
ship of plasma antioxidant levels (a-tocopherol, retinol, and
vitamin C) with the risk for breast cancer revealed that plasma
level of vitamin C was significantly lower in breast cancer sub-
jects when compared to control. However, when these data
were controlled for menopausal status, continent, and study
design, the significant relationship between plasma vitamin C
and breast cancer was only seen in case–control type of study.
Vitamin C may not be effective in treatment of active cancers
when used alone; its supplementation has been suggested to
enhance life quality and longevity of cancer patients; thus, it is
being studied as an adjuvant in cancer therapy. Some of the
proposed mechanisms include vitamin C role in protecting
cells from oxidative DNA damage, thus blocking initiation of
carcinogenesis. This is supported by several studies that
showed that plasma vitamin C at normal to high physiological
level (60–100 mmol l
1) concentration neutralized mutagenic
free radicals, reduced oxidative stress, and thus prevented DNA
damage. The evidence from population studies however does
not translate into similar results in randomized controlled tri-
als. A recent meta-analysis of RCTs and also a prospective
cohort study reported no survival advantages and no effects
of oral vitamin C supplementation on the incidence and mor-
tality from prostate cancer. On the other hand, vitamin C has
also been used in the treatment of malignancy by taking advan-
tage of its pro-oxidant capacity. Extracellular ascorbate can
destroy cancer selectively, with no effects on normal cells pos-
sibly through production of hydrogen peroxide. Pharmacolog-
ical doses of ascorbate can be attained only by intravenous (IV)
administration, due to the fact that orally administered vita-
min C is hampered by limited absorptive capacity of the intes-
tinal tract. Thus, this hypothesis provides a plausible
explanation for the failure of many orally supplemented stud-
ies discussed earlier. In a systematic review that covered 39
articles from RCTs, phase I and II, and observational study,
the authors concluded that high-quality studies on IV vitamin
C are limited; however, current studies provide some basis for
pharmacological benefits of IV vitamin C, thus justifying needs
for a larger clinical trials. Some of the positive effects of IV
vitamin C observed in these studies include a decrease in
chemotherapy-related side effects such as nausea, insomnia,
and constipation and improved time to relapse and quality of
life of the patients.
In a pilot RCT, administration of high doses of IV vitamin C
(75 g or 100 g per infusion) twice a week for 6 months during
chemotherapy and an additional 6 months after chemotherapy
among stage III/IV ovarian cancer patients leads to fewer side
effects/toxicities related to chemotherapy and less adverse
event when compared to the control group. Some of the pro-
posed mechanisms include that IV vitamin C acted as pro-
oxidant to induce DNA damage and depleted cellular energy
(adenosine triphosphate (ATP)). Moreover, pro-oxidant ascor-
bate stimulates ATM/AMPK pathway leading to mTOR inhibi-
tion and death of ovarian cancer cells. Another proposed
mechanism for IV vitamin C includes intermediating forma-
tion of extracellular hydrogen peroxide (H2O2). H2O2 diffu-
sion into tumor cells causes DNA and mitochondria to break
leading to cell death. Moreover, IV vitamin C therapy has also
been shown to work synergistically with chemotherapy drug,
gemcitabine, by sensitizing cancer cells to chemotherapy, lead-
ing to a synergistic cytotoxic response.
Despite some promising outcomes in many of the uncon-
trolled trials and case–control studies related to IV vitamin C,
these data are subjected to criticism. Risk of bias in these
studies is high due to heterogeneity of the study design, small
sample size, nonstandardized dosage, and incomplete infor-
mation on the pharmacokinetics and pharmacodynamics of IV
vitamin C.
To summarize, the evidences available to date provide an
interesting finding; however, they are not conclusive to suggest
any clinical benefits of vitamin C in the prevention and treat-
ment of malignancy.
Cataract
Cataract is characterized by increase in lens opacity or cloudi-
ness leading to decrease in vision and eventually blindness.
The World Health Organization revealed that cataract remains
the leading cause of visual impairments worldwide, responsi-
ble for 51% of all causes of blindness worldwide. During the
aging process, the lens undergoes biochemical, physiological,
and functional changes especially on its protein constituent as
a result of exposure to various insults including free radicals.
Vitamin C is naturally present in the lens at 50-fold of the
concentration found in the plasma. Several lines of evidence
indicate that aging process is associated with lower ascorbate
content of the lens that may compromise lens functions. Many
of the epidemiological studies demonstrated that higher vita-
min C levels are associated with diminished risk of cataract.
Interestingly, based on a systematic search and meta-analysis of
the observational studies, it was found that plasma ascorbate is
inversely associated with age-related cataract in the Asian
population but not in the Western population.
Data from RCTs, however, are not as encouraging. In a meta-
analysis that included nine randomized control trials involving
more than 117 000 individuals, supplementation with one or
more antioxidants (i.e., vitamin C, b-carotene, and vitamin E)
for the purpose of prevention of cataract yielded negative results.
The study concluded that there is no evidence to recommend
antioxidant supplementation as means to prevent or slow the
progression of age-related cataracts. Data from the Swedish
Mammography Cohort, involving more than 24 000 women
that were followed for 8.2 years, revealed even alarming results.
In this study, it was found that vitamin C supplement users
among women aged 65 had actually increased risk of cataract
by 38%.
 Ascorbic Acid: Physiology and Health Effects 273

Asthma and Respiratory Illnesses fracture. Globally, osteoporosis is responsible for more than
8.9 million fracture cases annually. It has been estimated that 1
Asthma is a chronic inflammatory airway disease characterized
in 3 women and 1 in 5 men over the age of 50 will experience
by variable, reversible airway obstruction and episodic symp-
osteoporotic fracture. Vitamin C plays an important role in
toms of wheezing, chest tightness, and/or cough. Asthma can
maintaining bone integrity by several mechanisms including
develop at any stage in life but often starts during early child-
mediating osteoclast differentiation and accentuating osteo-
hood. According to the Global Asthma Report (2014), it is
blastogenesis and bone collagen synthesis in osteoblasts, an
estimated that more than 300 million people suffer from
important process in bones remodeling, maintenance, and
asthma and 14% of the world’s children were likely to have
repair. In vitro and in vivo studies demonstrated that vitamin
had asthmatic symptoms last year. Asthma is often triggered by
C deficiency leads to decrease in bone matrix stability and
environmental insults, including common colds caused by
weakening bone structure. Quite a handful population-based
respiratory viruses.
cohorts demonstrated positive association of vitamin C intake
Vitamin C is one of the major antioxidants present in lung
and higher bone mineral density. However, data in human
tissue and lining fluid. This is to reflect its role in providing
intervention studies are scarce. An RCT involving 90 subjects
antioxidant protection against exposure to oxygen, as well as air
was conducted. The studied subjects were supplemented with
pollutant including ozone and nitrogen oxides. Similarly, vita-
either placebo (n ¼ 30), or 500 mg vitamin C þ 400 IU alpha-
min C may also implicate in inflammatory response during
tocopherol (n ¼ 30), or 1000 mg vitamin C þ 400 IU alpha-
asthmatic attack by providing protection against oxidative dam-
tocopherol for 12 months (n ¼ 30). The study showed that
age. A cross-sectional study indicates that ascorbate concentra-
the intervention with 1000 mg vitamin C and 400 IU of
tion in the lung of subjects with mild asthma is reduced. In a
alpha tocopherols led to significantly lower hip bone loss
population study involving more than 2000 patients, vitamin C
compared to control group. The extent of vitamin C role in
intake was associated with enhanced pulmonary function. A
preventing bone density loss is questionable due the presence
systematic review on intervention with vitamin C to reduce
of alpha-tocopherol. In short, more high-quality human inter-
common cold-induced asthma was done. In this article, the
vention trials are needed to rule out the therapeutic role of
author described three intervention studies involving a total of
vitamin C in preventing or delaying bone loss.
79 subjects. Vitamin C doses provided in all of the three studies
were ranged from 1 to 5 g day
1, so as the outcome measures
(one study on asthma exacerbation and the two studies on
bronchial sensitivity to histamine). These studies provide a pos-
Conclusion and Recommendation for Future Study
itive indication in which vitamin C supplementation is found to
reduce the occurrence of infection-induced asthma attacks by
Vitamin C has undoubtedly been proved to confer significant
78% and decrease bronchial hypersensitivity. However, further
antioxidant effects in in vitro and animal studies. Similarly,
study with larger sample size is needed to confirm these obser-
several lines of evidence indicate the potential of vitamin C
vations. Similarly, in another meta-analysis, it was found that
in counteracting with inflammation and oxidative stress, an
vitamin C is able to alleviate exercise-induced asthma.
underlying process of many chronic and acute diseases. Many
Another common respiratory illness is ‘common cold.’ The
of the epidemiological studies have generally shown potential
term ‘common cold’ basically refers to viral infection of the
therapeutic roles of vitamin C in the prevention and treatment
upper respiratory tract, characterized by a group of symptoms
of chronic diseases. However, this has not been translated, at
including nasal discharge and obstruction, sore throat, cough,
least conclusively, in many RCTs. This is attributed by the fact
lethargy, and fever. Although common cold is non-life-threat-
that our understanding of vitamin C effects at the molecular
ening, however, it is the leading cause of doctor visits and
level in human physiological system is incomplete. Neverthe-
absenteeism from work/school. Vitamin C has traditionally
less, future research in vitamin C should be streamlined by
been claimed to be useful in the prevention and treatment of
considering several issues including characteristics of study
the common cold. Despite a large number of publications on
population that may benefit from vitamin C intervention and
this aspect, the evidence to support the use of vitamin C
assessment of baseline vitamin C status, as patient with satu-
supplements to reduce the incidence and duration of common
rated levels of plasma vitamin C may unlikely benefit from
cold is relatively weak. In a recent meta-analysis involving 29
additional oral supplementation. With emergence of ‘omics’
trials that include more that 11 000 participants, it is found that
technology, it is hoped that this will address some of the
regular supplementation of vitamin C (200 mg day
1 or more)
limitations and controversies observed in animal and human
had no effect in reducing common cold incidence but had
studies by designing a high-quality mechanism-based interven-
modest effect in reducing the duration of common cold symp-
tion study.
toms. However, the authors recommend further evaluation in
special population including runners, skiers, swimmers, and
soldiers working in subarctic conditions given some positive See also: Anemia: Causes and Prevalence; Anemia: Prevention and
data on this population. Dietary Strategies; Antioxidants: Characterization and Analysis;
Ascorbic Acid: Properties, Determination and Uses; Bioavailability of
Nutrients; Citrus Fruits; Dietary References: US; Iron: Biosynthesis and
Osteoporosis and Fractures
Significance of Heme; Iron: Physiology of Iron; Oxidation of Food
Osteoporosis is a progressive deterioration of bone mass and Components; Storage Stability: Mechanisms of Degradation; Vitamins:
bone tissues leading to bone fragility and increased risk for Overview.
274 Ascorbic Acid: Physiology and Health Effects
Further Reading
Blass SC, Goost H, Tolba RH, Stoffel-Wagner B, Kabir K, et al. (2012) Time to wound
closure in trauma patients with disorders in wound healing is shortened by
supplements containing antioxidant micronutrients and glutamine: a PRCT. Clinical
Nutrition 31(4): 469–475.
Chen GC, Lu DB, Pang Z, and Liu QF (2013) Vitamin C intake, circulating vitamin C and
risk of stroke: a meta-analysis of prospective studies. Journal of American Heart
Association 2(6): e000329.
Cui YH, Jing CX, and Pan HW (2013) Association of blood antioxidants and vitamins
with risk of age-related cataract: a meta-analysis of observational studies. American
Journal of Clinical Nutrition 98(3): 778–786.
EFSA NDA Panel (EFSA Panel on Dietetic Products) (2013) Scientific opinion on dietary
reference values for vitamin C. European Food Safety Authority Journal 11(11):
3418–3468.
Finck H, Hart AR, Jennings A, and Welch AA (2014) Is there a role for vitamin C in preventing
osteoporosis and fractures? A review of the potential underlying mechanisms and current
epidemiological evidence. Nutrition Research Reviews 27(2): 268–283.
Fritz H, Flower G, Weeks L, Cooley K, Callachan M, et al. (2014) Intravenous vitamin C
and cancer: a systematic review. Integrative Cancer Therapies 13(4): 280–300.
Grosso G, Bei R, Mistretta A, Marventano S, Calabrese G, et al. (2013) Effects of vitamin
C on health: a review of evidence. Frontiers in Bioscience (Landmark Ed)
18: 1017–1029.
Hemila H (2013) Vitamin C and common cold-induced asthma: a systematic review and
statistical analysis. Allergy Asthma and Clinical Immunology 9(1): 46.
Juraschek SP, Guallar E, Appel LJ, and Miller 3rd. ER 3rd. (2012) Effects of vitamin C
supplementation on blood pressure: a meta-analysis of randomized controlled
trials. American Journal of Clinical Nutrition 95(5): 1079–1088.
Luo J, Shen L, and Zheng D (2014) Association between vitamin C intake and lung
cancer: a dose-response meta-analysis. Scientific Reports 4: 6161.
Mathew MC, Ervin AM, Tao J, and Davis RM (2012) Antioxidant vitamin
supplementation for preventing and slowing the progression of age-related cataract.
Cochrane Database of Systematic Reviews 6: CD004567.
McRae MP (2008) Vitamin C supplementation lowers serum low-density lipoprotein
cholesterol and triglycerides: a meta-analysis of 13 randomized controlled trials.
Journal of Chiropractic Medicine 7(2): 48–58.
Michels AJ and Frei B (2013) Myths, artifacts, and fatal flaws: identifying limitations and
opportunities in vitamin C research. Nutrients 5(12): 5161–5192.
NCCFN (2005) Recommended nutrient intakes for Malaysia. A Report of the Technical
Working Group on Nutritional Guidelines. Putrajaya, Malaysia: Ministry of Health
Malaysia.
Salonen RM, Nyyssonen K, Kaikkonen J, Porkkala-Sarataho E, Voutilainen S, et al.
(2003) Six-year effect of combined vitamin C and E supplementation on
atherosclerotic progression: the antioxidant supplementation in atherosclerosis
prevention (ASAP) study. Circulation 107(7): 947–953.
Relevant Websites
http://books.nap.edu/openbook.php?record_id¼9810&page¼R1 – DRI Dietary
Reference Intake for Vitamin C, Vitamin E, Selenium and Carotenoids, Institute of
Medicine.
http://www.health.gov/dietaryguidelines/2010.asp – Dietary Guidelines for Americans
(Vitamin C).
http://ods.od.nih.gov/factsheets/VitaminC-HealthProfessional/ – Vitamin C: Facts sheet
for health professional.
http://umm.edu/health/medical/altmed/supplement/vitamin-c-ascorbic-acid – Vitamin
C (ascorbic acid).