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Listen to this siteMonday 25 April 2005
This research project aims to evaluate the potential toxicity of vitamin C supplements in a large number of human volunteers at high doses.
Study Duration : October 2002 to September 2006
Contractor : King's College London
Some people take high doses of vitamin C supplements in the belief that 'the more you take the healthier you'll be'. However, over the last few years research has suggested that large doses of vitamin C may be harmful and have the potential to cause DNA damage (genotoxicity).
This project evaluated the potential toxicity of vitamin C supplementation in 200 healthy human volunteers at widely used doses (up to 2000 mg per day). Based on initial in vitro studies , candidate genes and proteins were selected alongside markers of DNA damage for investigation in a 10 week double-blind randomised controlled intervention study.
The aims of the
in vitro
arm of the project were to establish robust methodologies for analysis of intracellular vitamin C levels and to establish markers of oxidative DNA damage in a human lymphocyte cell line (CCRF-HSB-2) and in human peripheral blood mononuclear cells (PBMC). These methods were subsequently employed in the 10 week double-blind randomised controlled intervention study.
Vitamin C (ascorbic acid) is reversibly oxidized to dehydroascorbate (DHA) in the body, and DHA is more rapidly taken into cells than ascorbic acid. The
in vitro
studies showed dose-related increases in DNA damage with vitamin C and, interestingly, also with ascorbate-2-phosphate, a vitamin C derivative that is not oxidised to dehydroascorbate. Maximal levels of DNA damage were reached following 2 hours exposure to vitamin C but, in all probability due to its slower uptake into cells, only after 8 hours exposure to ascorbate-2-phosphate. As PBMC cannot be maintained for a sustained period in culture, the strong correlation observed between results from the cell line and PBMC suggests that they are a potentially useful model for PBMC when investigating
in vitro
toxicity.
In total 229 healthy volunteers (non-smokers) were recruited on to the double-blind randomised controlled intervention study, and 209 completed the 10 week supplementation period with 0, 100, 500 or 2000 mg vitamin C per day. Blood and early morning urine samples were taken at weeks 0, 1, 5 and 10. Samples were analysed for markers of DNA damage. Gene expression and proteomic studies were additionally performed on pooled blood samples.
Over the course of the 10 week supplementation trial intracellular vitamin C levels appeared to increase for all dose groups, including placebo. Although changes in the levels of the two measured DNA adducts in urine and blood were detected at various weeks of the study, these effects were not dose-related. In totality the data do not provide evidence for genotoxicity or cytotoxicity up to supplementation levels of 2000 mg vitamin C/day.
Gene expression and proteomic analysis of a limited number of pooled samples indicated possible beneficial effects on both priming the immune system (2000 mg/day dose group) and allowing adaptation to DNA damage by inducing up-regulation of genes associated with DNA-repair (1000 and 2000 mg/day dose groups). These findings will need to be confirmed in a larger and more focussed study.
Biochemical analyses of plasma from the 2000 mg/day dose group showed no effects on liver function, bone metabolism or electrolyte balance, with the exception of sodium which was elevated compared to baseline but still within the reference range. In addition, as plasma sodium levels can be affected by hydration status at the time of blood sampling (following a period of fasting in the current study), investigators were unable to confirm whether this was a real treatment-related effect.
Gastrointestinal effects are the most common adverse clinical events associated with acute, high doses of vitamin C. However, in the current trial reports of effects these were not common and were distributed equally across dose groups, including placebo.
Overall, results of the human volunteer trial show no adverse effects of supplementation with vitamin C up to doses of 2000 mg/day. Dose-related effects on levels of DNA damage were not observed, indicating, under the conditions tested, vitamin C does not affect DNA adduct formation or repair. Gene expression and proteomic analysis of a limited number of pooled samples indicated possible beneficial effects on both priming the immune system and allowing adaptation to DNA damage by inducing up-regulation of genes associated with DNA-repair. These interesting findings will need to be confirmed in a larger and more focussed study.
The FSA currently advises that eating a varied and balanced diet should provide the daily requirement of 40 mg vitamin C per day but that supplementation with 1000 mg or less per day is unlikely to cause harm. The results of the current study do not suggest a need to alter this advice, in terms of lowering the level below which harm in unlikely to occur.
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