Question: What do you think about this enclosed newspaper clipping of a recent announcement in the London Times that researchers have found that 500 mg dosages of vitamin C damages genes?

Answer: The study is real, but the conclusion that vitamin C is dangerous is unwarranted by the evidence presented. Of about 20 types of DNA damage that have been documented so far by scientists, only two types of DNA damage were measured. One increased while the other decreased. What does this mean? We don't know, for several reasons.

First, the increase in 8-oxoadenine levels (a marker of damage to adenine “A” nucleotides) was offset by a decrease in damage to 8-oxoguanine levels (which is a much better-researched marker of DNA damage to guanine “G” nucleotides). With offsetting trends, the net effect is not clear.

Second, DNA damage is an incredibly complicated process that is balanced by DNA repair mechanisms. According to estimates [Ames and Gold, 1991], each cell in the body can be expected to suffer approximately 10exp5 DNA-damaging events per day. For those “exponentially challenged” readers out there, that’s between 10,000 (10exp4) and 1,000,000 (10exp6) oxidative “hits” per cell per day. This suggests that DNA repair is an extremely robust and vitally important process to consider. Yet these researchers ignored it.

DNA repair enzymes slide along the DNA strand scanning for signs of damage. DNA is composed of A-T and C-G base pairs which are strung together in a double-stranded spiral called a helix. When these repair enzymes find an oxidized adenine (A) or guanine (G) nucleotide, they snip it out (the C and T bases remain intact to maintain the structural integrity of the DNA during repair) and an unoxidized (normal) adenine or guanine is put back in its place. The “snipped out” oxidized adenine and guanine are therefore markers of both DNA damage and DNA that has been repaired. Fundamentally, we are only interested in DNA damage that is not repaired. It is the unrepaired damage that is going to interfere with protein and enzyme function.

Third, we need to know the sites of damage because there are parts of DNA that do not get transcribed into proteins. These DNA sequences are either introns (which are snipped out during transcription) or initiation (control) sites which serve to activate and deactivate the transcription of “downstream” DNA. Some of these initiation sites are now known to contain iron, which provides a clear and well known mechanism by which vitamin C can damage DNA.

Vitamin C reacts with ferric iron (Fe+3, “oxidized” iron) to form ferrous iron (Fe+2, “reduced” iron). Ferrous iron reacts with hydrogen peroxide to form a hydroxyl radical, a potent oxidant and free radical. Hydroxyl radicals are not only powerful, they are extremely unselective. In other words, they tend to react with the first thing they bump into.

Scientists have known for many decades that extracted DNA has iron associated with it, but they didn’t know whether it was naturally present in native DNA or if it was an artifact of the chemical extraction process used to isolate the DNA. Now we know that the iron in DNA is there by design. It is actually imbedded in the center of the DNA double helix at certain loci (DNA sites) where it serves as an oxidation sensor to activate DNA in response to oxidative stress.

Because the iron is bulky, it distorts the outer shape of the DNA helix. This distortion depends on the oxidation state of the iron. Under reducing (non-oxidized) conditions, the iron is present in the ferrous state and the DNA helix is fairly tightly wound around the iron atom (it only bulges slightly from the iron “nugget” imbedded inside). But when the iron is oxidized to the ferric state, it opens up the DNA so that it is more easily expressed (i.e., transcribed into RNA and then into proteins). What proteins are expressed? Antioxidants! Heat shock proteins! These may include enzymes like SOD, catalase and glutathione peroxidase, plus other proteins that help mobilize and regulate the antioxidant defense system.

The ability of DNA to “sense” free radicals and oxidizing conditions in this manner is an essential aspect of our ability to maintain homeostasis (biological stability) and adapt to stress (environmental change). The fact that there may be temporary damage to DNA is a trivial price to pay for enhanced adaptability and increased survival.

Although much of the research into iron-DNA mechanisms is very recent, we do have some idea how DNA interacts with iron. In its activated state, the ferrous iron-DNA complex can react with vitamin C and hydrogen peroxide to produce a hydroxyl radical which can (and apparently often does) attack the DNA at the iron-binding site. Remember, hydroxyl radicals are highly unselective and tend to react with the first thing they hit. Since the iron-binding site is especially rich in A-T base pairs, it makes perfect sense that more damage would occur to A and T residues than C and G residues. In fact, I would be quite surprised if the researchers at the University of Leicester did not know about the iron sites and the increased proximity of adenine nucleotides before they conducted the study.

Quality scientific research is characterized by findings which: 1) are clinically significant, and/or 2) advance our basic knowledge. Although this study may trivially advance our basic knowledge, the clinical utility of this study is minimal. It would be a serious scientific mistake to presume that an increase in adenine oxidation will have any long-term adverse implications for cells, organisms or people. Until we know what oxidative damage is or is not being repaired, we cannot even begin to predict whether this specific effect of vitamin C on DNA would be expected to be positive or negative. DNA repair enzymes, like antioxidant enzymes, are readily inducible (i.e., producible on demand). I wouldn’t be surprised to discover that DNA repair enzymes are downstream of iron sites and thereby upregulated along with antioxidants. There are plenty of studies which show vitamin C to have a significant genome-stabilizing effect overall [see Fraga et al.]. I am certainly not reducing my intake of vitamin C based on this study. ——SWF

Continue on to Part II of this topic.