a two-edged sword?

Vitamin C could promote production of DNA-damaging compounds according to a study published in the June 15 issue of Science. Mutations caused by these compounds have been found in a variety of tumours. New findings by University of Pennsylvania researchers may help explain why vitamin C has thus far shown little effectiveness at preventing cancer in clinical trials. This dual activity of vitamin C has been studied by others both in vitro and in human subjects, notably by Joseph Lunec of the University of Leicester. But, the chemical mechanism behind this behaviour has not been elucidated until publication of the University of Pennsylvania study.Vitamin C, known chemically as ascorbic acid, can act as an antioxidant, consuming free radicals and thereby preventing free radical induced DNA damage. Free radicals are highly reactive chemical species produced by the reaction of oxygen with biological molecules, a chemical reaction that occurs constantly in cells. In addition to damaging DNA directly, free radicals can act indirectly. This indirect action begins when free radicals convert linoleic acid, the major polyunsaturated fatty acid in sunflower, grape, and safflower cooking oils, as well as the major polyunsaturated fatty acid in human blood, into an oxygenated analogue called a lipid hydroperoxide. When certain metal ions such as divalent iron or copper are present to act as catalysts, the lipid hydroperoxides degrade further, into species called lipid hydroperoxide-derived bifunctional electrophiles that are DNA-damaging agents dubbed 'genotoxins' These electrophiles may be capable of promoting their own formation through a COX-2 (cyclooxygenase) mediated pathway. These genotoxins react with DNA, switching one base for another in mutations (usually adenosine for thymine according to Ian Blair of the Center for Cancer Pharmacology, at the University of Pennsylvania) that have been found in human tumours.It has been suspected that vitamin C could be capable of making lipid hydroperoxides degrade into genotoxins, playing the same catalytic role as transition metal ions. To investigate this possibility, Blair's group added vitamin C to solutions of lipid hydroperoxides in test tube environments. They used vitamin C concentrations comparable to those found in people taking 200 milligrams of vitamin C supplement per day. They found that vitamin C was more than twice as efficient as transition metal ions at inducing the formation of a variety of DNA-reactive bifunctional electrophile genotoxins including 4,5-epoxy-2(E)-decenal, a precursor of etheno-2'-deoxyadenosine, a highly mutagenic lesion found in human DNA. Blair concluded, "Vitamin C-mediated formation of genotoxins from lipid hydroperoxides in the absence of transition metal ions could help explain its lack of efficacy as a cancer prevention agent.""It's possible that vitamin C isn't working in cancer prevention studies because it's causing as much damage as it's preventing, but that's really speculation at this point. What we can say is that vitamin C clearly doesn't work when you expect it to, and now we're in a position to see if that's what's happening in vivo," says Blair.DNA mutations can be repaired, however, and Blair said this shouldn't be interpreted as a claim that vitamin C causes cancer. Nor does he question the wisdom of eating a balanced diet rich in fruits, vegetables, and whole grains. Rich sources of vitamin C include citrus fruits, tomatoes, potatoes, cabbage and green peppers. "The logic being used [for vitamin C supplements] is that 'fruits, vegetables, etc. contain vitamin C; these foods prevent cancer; thus vitamin C prevents cancer," Blair said. "But our message is that it's the total diet that's important, not just one antioxidant in isolation. "He observes, "There is no substitute for a good diet. Vitamin C is not a magic bullet." Blair noted that while he himself used to take vitamin C supplements, he no longer does so.The dosage issue in taking vitamin C supplements is another contentious issue. Most dietary supplements contain far more than the recommended U.S. daily adult dietary allowance of 60 milligrams. Mark Levine and co-workers studied intake of different levels of vitamin C by healthy men. He found bioavailability was complete for 200 milligrams of vitamin C as a single dose. At single doses of 500 milligrams and higher, bioavailability declined and vitamin C excretion was elevated compared to lower dosages. Based on his study, Levine suggested that the recommended daily allowance of vitamin C be increased from 60 milligrams to 200 milligrams and noted "Safe doses of vitamin C are less than 1000 mg daily, and vitamin C daily doses above 400 mg have no evident value." In the context of Blair's more recent work, Levine's findings suggest that taking higher doses of vitamin C would not increase formation of genotoxins.Citing Levine's work, Blair said, "200 milligrams is the highest dosage that makes sense." This was the reason he used the vitamin C blood level concentration corresponding to this dosage in the study reported in Science. The next step for Blair's team is to determine whether vitamin C produces significant amounts of genotoxins in intact cells, and whether the intracellular genotoxins generate cancer-causing mutations. Anitra Carr and Blaz Frei of the Linus Pauling Institute and Oregon State University reported in 1999, "The data on vitamin C and DNA oxidation in vivo are inconsistent and conflicting." So this work is clearly needed.Other researchers agree that study of the behaviour of vitamin C within cells is needed. David Golde, Physician-in-Chief of Memorial Hospital at Memorial Sloan-Kettering Cancer Center and co-workers have shown that specific glucose transporter molecules are responsible for transporting vitamin C into cells. This discovery prompted Golde's team to explore whether glucose transporter molecules and vitamin C might function in cancer cells, as malignant cells consume more glucose than normal cells to obtain the energy they need to grow. Their laboratory studies with myeloid leukaemia cells showed that the cells accumulated high levels of vitamin C through their glucose transporters. "More studies need to be done to determine what the tumour cells do with the vitamin C once they get it," said David Agus, a participant in the study and an oncologist at Memorial Sloan-Kettering Cancer Center.

a two-edged sword?

Vitamin C could promote production of DNA-damaging compounds and may help explain why vitamin C has thus far shown little effectiveness at preventing cancer in clinical trials.

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