Do Antioxidants Cause Cancer?

Dr. Rhonda Patrick here. Today we're going to discuss antioxidants and their role in both normal healthy cells and in cancer cells. This is particularly relevant because stories have been circulating in the media discussing how antioxidants are not only bad for you, but they cause cancer. Let's start at the beginning. What are antioxidants and why are they biologically relevant? Disregarding all the external sources of damage such as smog, UVB radiation, smoking, there are 2 types of damage that are being produced inside of our bodies every single day. The first type of damage is called reactive oxygen species. Reactive oxygen species are produced from normal mitochondrial metabolism, and this is the way the cell produces energy through a process called oxidative phosphorylation.

The byproducts of normal mitochondrial metabolism are called reactive oxygen species, and they consist of superoxide anion, which also gets converted into hydrogen peroxide. In cases where people have metabolic syndrome or are obese, their mitochondria are working inefficiently and are even producing more of these reactive oxygen species. The second type of damage that's produced in our bodies is called reactive nitrogen species. And these are produced from immune cell activation, such as macrophages, which are activated in response to inflammatory cytokines that are produced when there's some sort of infection, like a bacterial infection in the body.

These macrophages then produce nitrogen oxide, and this nitrogen oxide reacts with superoxide, which is a byproduct of mitochondrial metabolism, to produce something called peroxynitrite, which is a very potent reactive nitrogen species that damages the cell. Antioxidants play a very important role in preventing both reactive oxygen species and reactive nitrogen species from damaging The DNA inside of your cell, the proteins inside of your cell, as well as the cell membrane. The first way in which these reactive oxygen and nitrogen species can wreak havoc on the cell is by causing damage to your DNA. DNA damage is a well-known initiator of mutations as well as chromosome damage.

When you get a mutation in a gene, it can often lead to the gene becoming inactivated and nonfunctional, which then results in an abnormal cell. We have certain genes within our cell that are able to detect this type of damage when it occurs, and they activate a pathway that ultimately ends in the death of these abnormal cells. These genes are called tumor suppressor genes because they do just that, they suppress the growth of tumor cells. Now, when you continue to have this damage over time, there's a constant flow of this damage occurring every day, and often it takes several decades, but eventually you may acquire a mutation in that very important tumor suppressor gene, therefore inactivating that tumor suppressor gene, so it's nonfunctional.

When that happens, any future damage that occurs will not have that cellular protective pathway activated, and so what ends up happening is that DNA damage ultimately will lead to the growth of abnormal cells, because they will not be, they will not be killed by tumor suppressor genes. In fact, over 50% of adult carcinomas are associated with nonfunctional tumor suppressor gene called p53. So the bottom line is DNA damage is a well-known initiator of cancer. In fact, this is one of the ways that smoking leads to cancer because smoking causes massive, massive DNA damage. So a good way to prevent cancer from occurring is to prevent that cancer-initiating DNA damage, and antioxidants have been shown to do just that.

With that said, there's been a recent sensation-grabbing editorial that was published in the New England Journal of Medicine stating that antioxidants in supplemental form may actually be doing more harm than good because they may cause cancer. Again, this is another case where context is very important, and in fact, the editorial and as well as the media did a very poor job in explaining both mechanism and context. Supplemental vitamin E has has been shown to prevent oxidation and prevent damage to DNA, which is a great thing if you don't have cancer because DNA damage ultimately can lead to cancer.

However, if you already have cancer, that DNA damage can activate those tumor suppressor genes that we talked about previously, and any cancer cells that still have a functional tumor suppressor gene will then result in the death of that cancer cell when that tumor suppressor gene is activated. In fact, a recent study in mice showed just this. Mice that already had lung cancer and were given various doses of supplemental vitamin E between 5 and 50 times the RDA actually resulted in an acceleration of that lung cancer growth. And that's because the supplemental vitamin E prevented oxidation, prevented DNA damage, and prevented the activation of functional tumor suppressor genes within those lung cancer cells.

So ultimately, those lung cancer cells didn't die, and they— this resulted in an acceleration of their growth. However, in the control mice that did not have cancer, the same doses of supplemental vitamin E did not cause cancer. In fact, it did just the opposite. It prevented DNA damage, a well-known cancer initiator. This is a perfect example of why supplemental vitamins can often be context-dependent And also why you shouldn't make huge overgeneralizations. Now, in the case of supplemental vitamin E, taking large doses of it, larger than what RDA recommends, which is currently 22.4 IUs a day, may not necessarily be a good thing for reasons that we're going to get to in just a little bit. The effects of these reactive oxygen and reactive nitrogen species don't just stop at DNA damage.

They also damage the proteins within your cell. Your DNA is the blueprint, which is then transcribed into RNA, which is then translated into protein. It's the protein inside of your cell that is doing everything, and the 3-dimensional structure of this protein is very important for its function. When the 3-dimensional structure is compromised from reactive oxygen and nitrogen species, this can often inactivate the protein such that it can't function properly. It also damages the ability of this protein to be cleared from the cell. And so the protein will end up hanging around and floating around inside the cell for extended periods of time, and which can then form aggregates with other proteins.

Protein aggregates have been shown to play an important role in neurodegenerative diseases such as Alzheimer's disease. Now lastly, these reactive oxygen and reactive nitrogen species have also been shown to damage the lipid bilayer of your cell membranes. Now all the cells in your body, including your neurons, contain a cell membrane. And these cell membranes have a certain fluidity to them. And this reactive oxygen and nitrogen species can damage that fluidity and make them more rigid. Now this happens with age. Our cell membranes become more rigid, but the more of these reactive oxygen and reactive nitrogen species that we're pouring out, the more rigid the cell membrane can occur at a more rapid rate.

There's proteins and transporters and receptors that are embedded within that cell membrane. And the fluidity of that membrane is very important for the structure, as well as the function of those proteins and transporters and receptors in that cell membrane. When the cell membrane becomes more rigid, it messes up the function and also the structure of many of those proteins. For example, within a neuron, neurotransmitter receptors are embedded in that cell membrane. And when that cell membrane becomes more rigid, the receptor is unable to bind to certain ligands as efficiently.

And that can affect neurotransmission and ultimately cause Our bodies produce natural antioxidant compounds and enzymes, some of which you may have heard of, such as glutathione and CoQ10, some of which you may not have heard of, such as superoxide dismutase. These natural antioxidant compounds and enzymes bind and sequester reactive oxygen and nitrogen species, preventing them from damaging the cell. In addition, we also require essential antioxidants from our diet, such as vitamins C and E. Because our bodies are unable to manufacture them.

Having explained some of the mechanisms by which oxidation and nitration can damage the cell, how antioxidants can prevent that damage, and the complexities between normal cells and cancer cells, I want to take a little bit of time and focus on vitamin E in particular. Approximately 60% of the US population does not meet the RDA requirement for vitamin E, which is 22.4 IUs a day. So these people have inadequate levels of vitamin E. I want you to keep this in mind when we discuss some of the negative effects of megadosing with vitamin E, particularly in a diseased population. There are 2 forms of vitamin E that are found within our tissues, alpha-tocopherol and gamma-tocopherol.

Alpha-tocopherol is the major form of vitamin E found in our plasma and our tissues, and it is a very potent antioxidant. That is, it is able to bind and sequester reactive oxygen species, preventing them from damaging the cell. Gamma-tocopherol is also found within our tissues to a lesser degree than the alpha-tocopherol form is, but the gamma-tocopherol serves a separate independent function. It's a potent anti-nitration, so it is very good at preventing anti-nitration from damaging our cell. In addition, the gamma-tocopherol form has also been shown to be an anti-inflammatory because it's been shown to inhibit cyclooxygenase COX activity. The major form of vitamin E that is found in supplements is alpha-tocopherol. In fact, supplements often leave out the gamma-tocopherol form.

It's been shown that megadosing with high levels of alpha-tocopherol can actually deplete your body's gamma-tocopherol levels, which is not a good thing. This has been shown empirically. So individuals that have been given very high doses between 10 to 20 times the RDA somewhere like 400 IUs a day for 2 years has been shown to deplete gamma-tocopherol levels by as much as 50%. This can have negative consequences. As I mentioned, the gamma-tocopherol vitamin E has an independent function from the alpha-tocopherol, so you really want to make sure you have levels of alpha and gamma-tocopherol inside of your cells.

A perfect example of the complex interplay between alpha and gamma-tocopherols in the context of cancer is the Selenium and Vitamin E Cancer Prevention Trial, also known as the SELECT trial, where men between the ages of 50 and 55 were given megadoses of alpha-tocopherol, about 400 IUs a day. Over the course of 7.5 years, these men had depleted their gamma-tocopherol levels by as much as 50%, and they had an increased incidence in prostate cancer. It's important to point out that inflammation also plays a very important role in cancer initiation, And gamma-tocopherol has been shown to inhibit inflammation. Another interesting point to this study is that only men with low selenium levels that were megadosing with alpha-tocopherol had the increased incidence in prostate cancer.

And in fact, those men that were taking the megadoses of alpha-tocopherol and supplementing with 200 micrograms of selenium a day were protected from having the increased incidence in prostate cancer. So what's going on here? Well, as it turns out, selenium is important for the function of a protein that also can get rid of damaging nitration species. This protein is called selenoprotein P, and it has much of the same activity as gamma-tocopherol has in that it can get rid of these damaging nitration species.

So if depletion of gamma-tocopherol levels in these men that were taking megadoses of alpha-tocopherol is partly responsible for the increased incidence in prostate cancer, it makes sense that supplementing with selenium at the same time would be able to rescue some of those damaging effects from reactive nitrogen species since those men wouldn't have had enough gamma-tocopherol around to do that. The bottom line is reactive oxygen and reactive nitrogen species are being produced inside your cells every day. These byproducts of just normal cell metabolism and normal immune function are wreaking havoc on the DNA, proteins, and on your cell membranes and lead to diseases of aging like cancer and neurodegeneration.

However, in the context of someone that already has cancer, taking supplemental antioxidants can actually prevent the activation of tumor suppressor genes because it prevents DNA damage. Tumor suppressor genes play an important role in killing cancer cells. In addition, taking megadoses of alpha-tocopherol supplements can deplete gamma-tocopherol levels in your tissues, Gamma-tocopherol has potent anti-nitration and anti-inflammatory activity. Whole foods such as almonds, pecans, and avocados are a great dietary source of all forms of vitamin E. If one chooses to supplement with vitamin E, it's important to make sure the supplement has both alpha and gamma-tocopherols present, and it would be important to not megadose with vitamin E and make sure you stick to levels that are around the RDA, which is 22.4 IUs a day. I'm Dr. Rhonda Patrick, and I'll catch you next time.