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Research Newsletter-Fall/Winter 2008

ZINC: FROM DIABETES TO CANCER

An interview with Emily Ho, Ph.D.
Associate Professor of Nutrition and Exercise Sciences
LPI Principal Investigator

Q. How did you decide on a career in nutritional science?

A. At the University of Guelph in Ontario, Canada, I majored in biochemistry and biology. One of my first lab experiences was in a free radical lab with someone working on the antioxidant enzyme superoxide dismutase and Lou Gehrig's disease. I worked in John Phillips's lab, and one of his collaborators was Tammy Bray, who was in the nutrition department and is now a Dean at Oregon State University and a member of LPI. She was also really interested in free radical metabolism and more of an applied researcher rather than a geneticist. I really liked the research and free radical theory of disease, so I started to lean towards how nutrients can really make a big impact on disease. I did an undergraduate project with Tammy and switched over to the nutrition program after my sophomore year.

Q. Your early work was on diabetes. What is the difference between type 1 and type 2 diabetes?

A. The common name for type 1 diabetes is juvenile onset diabetes, but that's changing now that type 2 diabetes is affecting juveniles. In type 1 diabetes, there is an immune destruction of the insulin-producing beta cells in the pancreas, so these people can no longer produce insulin. Type 2 diabetes is more of an insulin-resistance problem. These people can still produce insulin, but it doesn't function to respond to elevated blood glucose anymore. So the two are very different even though both result in high blood glucose that causes problems like heart disease and renal failure.

Q. What causes the destruction of beta cells in juvenile diabetes?

A. That's the golden question. It's unknown what triggers the immune attack on the beta cells. Years ago we weren't really interested in how that happens as much as in how the immune response could be mitigated. Antioxidant supplementation was one strategy to help stop some of the consequences of the immune attack on the beta cells.

Q. Is that because reactive oxygen species are implicated in the destruction of these cells?

A. Exactly. Immune cells produce reactive oxygen species to kill pathogens like viruses. In type 1 diabetes, the immune system is activated, and macrophages, monocytes, and neutrophils start generating lots of oxidants to try to destroy the pathogen, and the beta cells are unfortunate victims of the attack.

Q. Why are beta cells vulnerable to these oxidants early in life but not in adults?

A. That's unknown. The islet cells are uniquely sensitive to oxidative stress, especially early in life. For example, if a premature infant is put into a high oxygen environment because his or her lungs are not developed, lots of oxidants are produced and pancreatitis may occur. The pancreas becomes inflamed because it doesn't yet have its full complement of antioxidant defense mechanisms in place.

Q. And that can result in the onset of juvenile diabetes?

A. Well, the association has not been fully established, but it is a working hypothesis. Unlike the lungs, the pancreas is susceptible to oxidative stress, probably because its protection by antioxidant enzymes and micronutrients has not fully developed.

Q. Has that been studied in animals?

A. Certain chemicals that generate reactive oxygen species can selectively destroy the beta cells in rodents. A specially bred mouse develops type 1 diabetes very similar to humans through an autoimmune attack that's age dependent.

Dr. Emily Ho and her son Ryan

Q. What dietary strategies might be important in influencing the risk for type 1 diabetes?

A. We study zinc, largely because zinc is an antioxidant and also plays a critical role in insulin storage. Insulin is stored as a zinc crystal inside the islet cells in the pancreas, so it has an important function to preserve insulin function. Type 1 diabetes has a genetic component, but we know from studies of twins that it's not nearly as strong as some environmental factors.

Q. Has anyone ever examined antioxidant status in youngsters to find out if it is associated with protection against the development of type 1 diabetes?

A. People have tried, but it's a really difficult question. Diabetes itself causes high glucose that generates a lot of oxidative stress. By the time a child is diagnosed, more than 90% of their beta cells have already been destroyed.

Q. You published a study showing that N-acetylcysteine inhibits the activation of inflammatory molecules in mice. What is that compound?

A. We used it as a pro-drug to produce glutathione in the mice. Glutathione is a very important thiol-based antioxidant in the body, but if you take it as a supplement, it will get destroyed in the digestive system. Our strategy was to provide a precursor to glutathione so that more of it will be made in the body.

Q. Does N-acetylcysteine have any toxicity?

A. As far as I know, no significant side effects or toxicity have been reported.

Q. How does glutathione affect inflammation?

A. NF-κB is a transcription factor that turns on a lot of genes involved in the immune response, acting as a master regulator of immune response. NF-κB is redox sensitive—oxidative stress can activate it, which causes the expression of genes that cause inflammation. That, in turn, produces more oxidative stress that further amplifies the process. Glutathione or other antioxidants may help break that cycle by stopping the oxidative stress, attenuating NF-κB activation, and breaking the endless cycle of self-propagating chronic inflammation. We think that zinc also inhibits NF-κB activation.

Q. How might zinc protect against diabetes?

A. Zinc plays a big role in helping to maintain a healthy immune system. It also acts as an antioxidant and stops some of the proinflammatory effect of NF-κB.

Q. Are diabetics zinc deficient?

A. Not many studies have examined zinc status in diabetics. The main problem is that zinc status is very difficult to assess—there is really no good biomarker for marginal zinc deficiency, which is what we have in the United States. In developing countries where there is a lot of severe zinc deficiency, there also is an increased incidence of chronic infections.

Q. In some countries people consume a lot of phytic acid from cereals and grains that binds to zinc, making it biologically unavailable. Is diabetes common in those areas?

A. Diabetes is not a very significant problem for countries like Iran and Bangladesh, where phytic acid-containing foods are commonly consumed. In those countries gastrointestinal and respiratory infections are some of the major causes of death, so they are more intensely studied. Also, in many of those countries caloric intake is low compared to Western countries.

Q. How does zinc affect DNA damage and repair?

A. Zinc is a really interesting nutrient because it does such a wide variety of things. Its antioxidant function may help protect from oxidative damage associated with cancer risk. Zinc is also a part of many different metalloproteins, some of which are involved in DNA repair and replication, so when you don't have adequate zinc, a lot of these enzymes might not function properly and the ability to repair DNA is impaired.

Q. Do most people get enough zinc in their daily diet?

A. Most people get enough zinc. However, according to the latest NHANES data, which is a huge database of dietary intake patterns in the United States, up to 12% of the U.S. population is not getting the recommended dietary intake of zinc. In the elderly, the number is closer to 50%. So, in older individuals, zinc deficiency is an especially important problem.

Q. The RDA of zinc for adult men is 11 mg/day and for adult women, 8 mg/day. How are those RDAs determined, and why is there a difference in the RDA for men and women?

A. The way that the RDAs are determined is a long story. There is a lot of debate about whether those values are actually high enough. Zinc is a really tough nutrient to study in humans. We try to establish the RDAs based on human data from zinc balance studies. Zinc can be radiolabeled in order to trace it, and then we can see how much stays in the body and how much is excreted. If you have sufficient zinc, more will be excreted, but if you have low zinc status, more will be retained. Some animal models are used, but it's difficult to extrapolate to humans. The main reason why there are differences between men and women may be average body size, which, of course, has changed appreciably in recent years.

Q. The tolerable upper level of intake (UL) for zinc is 40 mg/day for both men and women. Do you think that's reasonable?

A. I think that is reasonable. Zinc itself is actually very non-toxic. The main problem with zinc is that it competes with other minerals. So the UL for zinc is based on its effect on copper absorption. There is a chance that you might compromise copper status if you exceed the UL for zinc.

Q. It has been suggested that too much iron or copper may be detrimental to health because it accumulates, especially in post-menopausal women and in men. Do we need to worry about zinc accumulation with age?

A. No. Unlike iron and copper, which can be pro-oxidant and cause oxidative stress at high concentrations, zinc isn't detrimentally reactive. Again, the main problem with excess zinc is interference with other metal nutrients. There is also little ability to store zinc in the body.

Q. You mentioned that zinc has indirect antioxidant function, probably as a component of copper-zinc superoxide dismutase and in other ways. How do you study this?

A. We're using cell cultures, rodents, and some human subjects to check how zinc intake affects total antioxidant capacity and oxidative stress. We do that by measuring a biomarker of oxidative stress called F2-isoprostanes, which are formed from the oxidation of arachidonic acid, an omega-6 fatty acid.

Q. Are there any symptoms of marginal zinc deficiency?

A. Yes, there are a lot of symptoms of marginal zinc deficiency. Zinc is involved in so many processes that symptoms of marginal deficiency are pretty nondescript, unlike vitamin C, where classic deficiency symptoms are clear. With zinc, so many different proteins can be affected, and you see very generalized deficits in immune function, slow growth and general malaise in children, or gastrointestinal problems.

Q. Do you think that zinc lozenges may be helpful in treating the common cold?

A. I think that the evidence is somewhat equivocal. I doubt that there is a strong, direct antiviral effect, but zinc does affect immune function. It's possible that marginal zinc deficiencies are going relatively undetected in the U.S. When you take the zinc supplements, you start to restore your zinc status, and that helps to boost your immune system. Some research has used zinc sprays, but one of its side effects is a loss of smell, sometimes permanently.

Q. You have done a lot of work with zinc and prostate cancer using cell cultures. What have you found?

A. The prostate has the highest concentration of zinc of all the soft tissues in the body—bone is the only other tissue that has more zinc. The prostate accumulates zinc, but we don't know why. In prostate cancer, the zinc levels dramatically drop dose-dependently with disease progression. We want to understand these phenomena better.

Q. Do zinc levels decline with age in men?

A. We're looking into that. As I mentioned, zinc status in humans is really difficult to assess, but there is some evidence that zinc levels decrease with age. We think that absorption may change with age. Older people eat less, and they are not able to absorb as much zinc. Most of the studies have been done in women. If you give zinc supplements to young women and older women, plasma zinc levels will increase in the young but not in the older women. With men, it doesn't look like zinc supplementation is going to be a cure for prostate cancer. We haven't seen much effect of zinc in decreasing cancer in our rodent studies, but we have found that low zinc levels cause problems in the prostate with respect to oxidative stress, DNA damage, and mutations that could increase the risk for cancer.

Q. Does zinc have any effect on prostate cancer malignancy?

A. The more aggressive cancers seem to have less zinc. One problem is that the cancer cells have adapted to a low zinc status, so if you give zinc, they are more resistant. We have been a little bit disappointed with the fact that once you have cancer, zinc doesn't help much. On the other hand, zinc may play an important role in preventing prostate cancer.

Q. What are the most effective dietary strategies to protect against prostate cancer?

A. There's no magic bullet, but consumption of fruits and vegetables is associated with decreased risk. Our research suggests that cruciferous vegetables might be helpful. People in Asia have a very low incidence of prostate cancer, but when they move to the United States, it dramatically increases because of dietary changes. Also, there has been a low prostate cancer risk in China, but as they become more industrialized, there is a slow but steady increase in prostate cancer. Eating a lot of fat or red meat seems to increase the risk. Obesity is a risk factor for prostate cancer partly because of its associated inflammation and hormones that may change with increased adiposity.

Q. You found that elevated estrogen levels in men who have high testosterone levels are associated with an increased risk of prostate cancer. Why?

A. The diet may affect that. For example, soy compounds can affect estrogen levels. It seems to be the ratio that's important, not necessarily the absolute amount. The higher estrogen ratio is more pro-inflammatory in men.

Q. Are you interested in a whole food approach rather than supplements?

A. Yes. The substances in supplements may not be absorbed as well as those in food. And foods, like tomatoes, have not only lycopene, but vitamin E and some other polyphenolic compounds that act synergistically and target different cellular pathways. In some studies, a lycopene supplement was not as effective as freeze-dried tomato in preventing cancer.

Q. Your recent studies have examined the role of sulforaphane in tumor suppression. What is sulforaphane, and how does it work?

A. Sulforaphane is a chemical found in plants, specifically in cruciferous vegetables like broccoli, cauliflower, and cabbage. It's an isothiocyanate and works through multiple mechanisms. Paul Talalay's group at Johns Hopkins did a lot of the groundbreaking work with sulforaphane. It helps get rid of carcinogens through a detoxification mechanism in the early stages of carcinogenesis. The problem is that you don't usually know when you were exposed to possible carcinogens, so the timing of exposure and sulforaphane ingestion is problematic. By the time of cancer diagnosis, initiation is an historical event. There is interest now that sulforaphane may act in the post-initiation phase—not just getting rid of carcinogens but actually stopping some of the uncontrolled proliferation of cells. It may stop the proliferation by affecting epigenetics—a process where the environment affects gene expression without changing the DNA code.

Q. Specifically, you found that sulforphane inhibits histone deacetylase. What is that process, and why would it protect against cancer?

A. Histones are proteins around which DNA winds. When histones are acetylated, genes are turned on. When histone deacetylases remove the acetyl groups, genes are turned off. In cancer, histone deacetylases that remove the histone acetylation group are overactive. So genes that are normally active to help combat cancer, like tumor suppressor genes, are turned off. Histone deacetylase inhibitors like sulforaphane reverse this process so that tumor suppressor genes can be turned on.

Q. Has sulforaphane been tested in humans?

A. This is very much in the early stages. We start out with cell cultures and animal models. Both our group and the Talalay group have started to look at sulforaphane in people, checking safety, toxicity, and metabolism.

Q. Would the amount of sulforaphane in vegetables that we consume be effective, or do you think that supplements may be necessary?

A. The current recommendation is to consume five to nine servings of fruits and vegetables per day, but the amount of sulforaphane in those vegetables may not be sufficient to get the desired effect.

Last updated January 2009