Does Vitamin C Act as an Antioxidant or Pro-Oxidant?
By Nina Mikirova, Ph.D.
High doses of vitamin C are administered intravenously by complementary and alternative medicine practitioners. Studies, including studies at The Center, demonstrate that high doses of intravenous vitamin C may have a role in the treatment of cancer.
Intravenous doses can produce blood plasma concentrations 30- to 70-fold higher than the maximum tolerated oral doses.
According to the study at The Center, only intravenous vitamin C produces high blood plasma concentrations that might have antitumor activity. The intravenous doses can produce blood plasma concentrations 30- to 70- fold higher than the maximum tolerated oral doses.
An infusion of 15 g of vitamin C during 45 minutes usually produces a maximum blood plasma concentration of about 120 mg/dL. Infusion of 60 g of vitamin C over 160 minutes produces a maximum concentration in blood plasma near 300 mg/dL.
The level of cytotoxicity of vitamin C to tumor cells was determined in vitro (in the test tube). Vitamin C killed cancer cells at extracellular concentrations of 200-300 mg/ml for monolayer cells and at higher concentrations for a three-dimensional tumor model. The level of vitamin C that can produce tumor cell death can be reached only by intravenous administration.
In addition, we found that vitamin C is preferentially toxic to tumor cells.
The main reason for this is the content of the enzyme catalase, which is 10- to 100-fold greater in normal cells than in tumor cells. Another aspect of high doses of ascorbate treatment is the effect on lipids and proteins in human blood plasma. As blood plasma plays a central role in the transport and fate of lipids, the mechanisms that act to control oxidative stress represent a major line of defense regulating general health status. Typical damage resulting from the attack of free radicals in blood plasma is the oxidation of proteins and lipids. Free-radical damage and lipid peroxidation are present in several disease states, including cancer, rheumatoid arthritis, drug associated toxicity, as well as in the degenerative processes associated with aging.
Protection of the blood plasma against oxidative stress at low concentrations of vitamin C has been a subject of many investigations. These studies demonstrated that low concentrations of vitamin C do not act as a pro-oxidant towards lipids and proteins in human blood plasma, even under oxidizing conditions. Vitamin C can prevent lipid peroxidation induced by aqueous peroxyl radicals, by activated neutrophils, and by other sources.
But the effect of high doses of vitamin C on antioxidant defenses and lipid peroxidation in human plasma has been the subject of debate. Discussions were about the danger of mega doses of blood plasma is very low.
The protective effect of blood plasma against oxidative damage is due to the presence of antioxidant molecules and to the presence of various metal binding proteins. In addition, the blood plasma is protected by the antioxidant systems, which include vitamin C, alpha-tocopherol (vitamin E), beta-carotene, uric acid, bilirubin, and trace amounts of antioxidant enzymes such as glutathione peroxidase and superoxide dismutase.
Exposure of blood plasma to aqueous peroxil radicals leads to oxidation of endogenous vitamin C followed by the depletion of other antioxidants. When vitamin C is consumed completely, very small concentrations of hydroperoxides of blood plasma phospholipids, triglyceride, and cholesterol ester appear simultaneously even though some other antioxidants are present in blood plasma.
The goal of our research was to assess the effect of high doses of vitamin C supplementation on the antioxidant capacity of blood plasma and resistance of the blood plasma to oxidative stress. For this purpose, we determined the level of antioxidant capacity of blood plasma by incubation of plasma with a free radical initiator and measured the Total Radical-Trapping Antioxidant Parameter.
The study was performed in vitro (test tube) and in vivo (human body). In vitro, vitamin C was added in the blood plasma with concentrations of 50uM-5mM. This range includes a typical natural concentration of vitamin C in blood plasma (about 50 uM) and the level of vitamin C in blood plasma after 15 g of intravenous vitamin C treatment. According to our data, the addition of vitamin C in the reaction mixture protected blood plasma from oxidation.
The addition of vitamin C in blood plasma increased the antioxidant capacity of blood plasma for all analyzed concentrations of vitamin C. Other researchers found a sequence of the antioxidant consumption and lipid peroxidation similar to ours in blood plasma exposed to other types of oxidative stress, such as activated neutrophils, the gas phase of cigarette smoke, and superoxide radicals or hydrogen peroxide generated by other sources. Under all these types of oxidative stress, vitamin C formed the first line of anti-oxidant defense.
To evaluate whether intravenous vitamin C infusion (IVC), which may have antitumor activity, does not have pro-oxidant effects on blood plasma lipids and proteins, the same assay was applied to measure the antioxidant capacity of blood plasma for several patients and volunteers before and after treatments by IVC.
We found a difference in the level of antioxidant protection before IVC for different patients. The lower level of antioxidant capability of blood plasma was found for patients with a higher level of oxidative stress. Oxidative stress was evaluated for these patients by measuring the level of hydrogen peroxide or the level of oxidative stress in red blood cells. An increased level of oxidative stress increases consumption of antioxidant molecules and enzymes.
The level of antioxidant protection after 15 g IVC was measured for several patients and healthy volunteers. According to these measurements, 15 g of IVC improved the antioxidant status of blood plasma and resistance to oxidative stress at least 5 times. The level of antioxidant protection of blood plasma depended on the dosage of IVC. To assess the effect of a dosage of IVC on blood plasma antioxidant status, we analyzed data from several patients treated by 15 g of IVC and patients treated by 25 g of IVC to find dependence of the antioxidant capacity of blood plasma on the level of vitamin C in the blood plasma. Upon incubation of the blood plasma from patients treated by IVC with a free radical initiator, vitamin C concentrations were positively correlated with the time of protection preceding detectable lipid peroxidation.
Our data suggest that in a state of acute or chronic oxidative stress, vitamin C supplementation could be helpful in preventing the formation of hydroperoxides, some of which cannot be detoxified by endogenous blood plasma activities and might cause damage to critical biomolecules.