To “C” or Not to “C”
The Dual Role of Vitamin C as an Antioxidant and Pro-Oxidant
By: Theodore Hersh, M.D., AGAF, MACG
Copyright
“Antioxidants” and “Free Radicals” are terms that are becoming most familiar to
the health conscious consumers. Healthcare providers recommend antioxidant rich
foods such as fruits and vegetables as well as additional dietary antioxidant
supplementation. These recommendations are based on a number of clinical studies
that reveal the value of antioxidants in preventing disease and prolonging life. Various
epidemiologic studies have confirmed that individuals with low levels of antioxidants in
their bodies are at a greater risk for developing cardiovascular diseases and various
types of cancer particularly prevalent as we age, consume fatty foods and are exposed
to ultraviolet radiation, tobacco and other environmental pollutants. This phenomenon is
related to the generation excess of toxic free radicals, since these are unstable
molecules that cause damage to cell function and to vital molecules like DNA, proteins
and lipids. Free radicals are also known as pro-oxidants. It is the function of antioxidants
to neutralize and scavenge these pro-oxidants into non-toxic compounds and thereby
prevents oxidation reactions in the body.
The imbalance between levels of antioxidants (too few) and free radicals (too
many) leads to a condition known as oxidative stress, which is the cause of damage to
cells and body fluids.
Although antioxidants unquestionably
are valuable in prevention of disease and
prolonging a healthy longer live span, some
clinical studies have suggested that singular
antioxidants may become pro-oxidants under
special circumstances. The chemical
characteristics of the individual molecules
determine the capacity for each to be the
beneficial antioxidant or the detrimental prooxidant. Antioxidants work best when taken
together, so that they continue to regenerate one another, much the same way as they
work in the cells. Antioxidants are the “reducing” agents while free radicals are the
“oxidizing” chemical agents. Examples of oxidation include nails that rust or cut apples
that become oxidized and turn “brown”.
The nutrient vitamin C, ascorbic acid, may have either antioxidant or pro-oxidant
activity in the body. This property is related to its metabolic function in reductionoxidation (called redox) reactions. For
example, when the antioxidant vitamin C
molecule neutralizes a free radical, it is itself
oxidized and becomes a pro-oxidant.
In order to prevent the build up of the
oxidized vitamin C, the cells use their most
important antioxidant partners, the Thione
Complex™ to regenerate the vitamin C to its
antioxidant property. This cycle keeps the
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antioxidants regenerated and avoids pro-oxidant damage. It is thus vital for our
antioxidant stores to be maintained to monitor the free radicals and prevent these toxins
from causing chronic diseases and from enhancing the aging process. Combinations of
antioxidants have been shown to be superior to the administration of single antioxidants
in preventing diseases and cancer. For these reasons, it is of greater value to
supplement diets with synergistic antioxidants to assure the cycle maintains the nutrients
as antioxidants. Indeed, in various clinical
studies high amounts of vitamin C have been
associated with breaks in DNA molecules,
which are the precursor damage o mutations
and malignancy. In smokers, the plasma
levels of the oxidized vitamin C are high
compared to near absent levels of this prooxidant in the non-smokers. This results from
the free radicals in cigarette smoke and from
lower levels of the other antioxidants that
recycle vitamin C in smokers. This finding of
high levels of oxidized vitamin C have also
been recorded in patients with diabetes, especially those with poorly controlled diabetes.
The oxidized vitamin C in these cases may promote the cardiovascular complications
occurring in patients with diabetes by oxidation of the low-density lipo-proteins that carry
the “bad” cholesterol.
In our bodies, most of the free radicals and reactive oxygen species that need to be
scavenged or neutralized by our own endogenous antioxidants are oxidizing agents.
Human cells generally function in a reduced state. These antioxidants are reducing
agents; in the process of neutralization of the free radical, the reducing agent becomes
oxidized and needs to be regenerated to its reduced status to become anew the
antioxidant. If not regenerated, the oxidized agent may itself act as a free radical. This
has been demonstrated particularly for vitamin C. If the intakes of vitamin C are very
high, ascorbic acid (the antioxidant vitamin C) remains in its oxidized form as
dehydroascorbic acid and an ascorbate free radical, which may then cause damage to
macromolecules and cells. Metals, such as iron, also promote the oxidation of ascorbic
acid. The dehydroascorbic acid may cause oxidative damage to DNA. This
phenomenon was also documented in groups of volunteers who received cosupplementation of iron and vitamin C.
Various other studies have confirmed that ingestion of vitamin C alone and in high
quantities may act as a pro-oxidant. Podmore and co-workers gave 500mg. of this
dietary supplement to 30 healthy volunteers for six weeks and assessed oxidative
damage to blood lymphocytes. At the end of the study period there was laboratory
evidence of an increase in 8-oxo-adenine, reflecting a potential mutagenic lesion. In this
study, this bio-marker returned to normal, pre-vitamin C treatment level, six weeks after
discontinuing this dietary supplement. Most recent studies by Blair and colleagues from
the University of Pennsylvania have also demonstrated that vitamin C may accumulate
as a pro-oxidant and induce oxidative changes. They showed lipid hydroperoxide
decomposition in various units of DNA, resulting in mutations. Such observations may
help decipher the clinical studies where the administered vitamin C by acting as a prooxidant did not protect against the development cancer. The authors conclude that the
formation of genotoxins from lipid hydroperoxides mediated by vitamin C even in the
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absence of transitional metal ions may help explain why vitamin C is not always an
effective cancer chemoprevention agent.
In summary, the nutrient vitamins we consume in foods and dietary supplements,
particularly vitamin C, have dual roles as antioxidants and pro-oxidants. These functions
depend on a cell’s environment maintaining its antioxidant stores so that these
molecules are continuously recycled. To preserve healthy bodies, it is imperative to
prevent antioxidants from accumulating as pro-oxidant molecules. The regeneration of
vitamin C depends on the Thione Complex™. This group of endogenous antioxidants
form an interacting network that maintain each other as vital protectors in the body from
the ravages that free radicals may cause. In this manner, the antioxidants act as
defenders against cell damage and thereby help prevent many chronic diseases.
Antioxidants are also associated with longevity, hence the value of heeding the advice of
nutritionists to consume diets high in fruits and vegetables and supplement these with
the synergistic group of antioxidants as exist in all our cells.
Selected References
1. Banerjee, A, Blood Dehydroascorbic Acid and Diabetes Mellitus in Human Beings,
Ann Clin Biochem, 1982; 19:65-70
2. Dhariwal, KR, et al, Ascorbic Acid And Dehydroascorbic Measurements In Human
Plasma And Serum, Amer J Clin Nutr 1991; 54: 712-716
3. Halliwell, B, The Antioxidant Paradox, Lancet 2000; 355: 1179-1180
4. Kim, HS, Lee, BM, Protective Effects of Antioxidant Supplementation on Plasma
Lipid Peroxidation in Smokers, Toxicol Environ Health 2001; 63:583-598
5. Lee, BM, Lee SK, Kim, HS, Inhibition of DNA damage, 8 OHdG, and Carbonyl
Contents in Smokers Treated with Antioxidants, Cancer Lett 1998; 219-227
6. Lee, SH, Oe, T, Blair, IA, Vitamin C Decomposition Of Lipid Hydroperoxides To
Endogenous Genotoxins, Science 2001; 292-2083-2086
7. Lykkesfeldt, J, Christen, S, Wallock, LM et al, Ascorbate is Depleted by Smoking and
Repleted by Moderate Supplementation: A Study in Male Smokers and NonSmokers with Matched Dietary Antioxidant Supplementation, Amer. J. Clin. Nutr.
2000; 71:530-536
8. Lykkesfeldt, J, et al, Ascorbic Acid and Dehydroascorbic Acid as Biomarkers of
Oxidative Stress Caused by Smoking, Amer J Clin Nutr 1997; 65:955-963
9. May JM, Qu, Z et al, Recycling Vitamin C from its Oxidized Forms by Human
Endothelial Cells, Biochem Biophys Acta 2003:1640:153-161
10. Podmore, ID, Griffiths, HR, Herbert, KE, et al, Vitamin C Exhibits Pro-Oxidant
Properties, Nature 1998; 392:359
11. Rehman, A, Collis, CS, Yang, M, et al, The Effects of Iron and Vitamin C CoSupplementation on Oxidative Damage to DNA in Healthy Volunteers, Biochem
Biophys Res. Common 1998; 246: 293-298
12. Schwartz, JE, The Dual Roles of Nutrients as Antioxidants and Pro-Oxidants,
J Nutrition 1996:126:1221-1227
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