For researchers who study the cancer-inhibiting mechanisms of selenium, the scientific literature generally comes in two flavors. Selenium is seen as either a beneficial scavenger of DNA-damaging oxygen free radicals or as a potent inducer of apoptosis that eliminates damaged, potentially cancerous cells.
Now a third flavor could be on the menu. Scientists at Indiana University in Indianapolis reported recently in the Proceedings of the National Academy of Sciences that high levels of selenomethionine, the primary organic form of selenium, prompts cells in culture to initiate DNA repair, a key mechanism in preventing cancer. The group, led by Martin Smith, Ph.D., shows that the nutrient indirectly switches on a DNA repair subpathway controlled by the regulatory protein p53.
The finding raises the intriguing, but still scientifically murky, possibility that people with functional p53 could boost their capacity for DNA repair by simply increasing their dietary intake of selenomethionine by, for example, eating Brazil nuts, a plentiful source of the amino acid. The idea hinges in part on previous studies indicating that some people are naturally more proficient at DNA repair than others and that this inherent difference can be correlated with cancer risk.
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Common Trace Element
Selenium is a common trace element in alkaline soils that enters the food chain via wheat, corn, and other forage plants. Following the discovery of selenium during the early 1800s in the sediment of a Swedish sulfuric acid plant, the mineral was considered for decades to be extremely toxic to animals at high levels and a possible carcinogen. By the late 1950s, however, scientists had concluded otherwise. They found that selenium is actually an essential component of the human diet that is necessary for growth and fertility.
On the heels of this discovery, scientists observed that people who lived in areas of the United States with moderate or high levels of selenium in their forage crops had lower death rates from various cancers than people in regions with low-selenium forage crops. This unexpected finding triggered a flurry of follow-up studies around the world that yielded generally supportive, but sometimes contradictory, epidemiologic data.
Then, in 1996, the late Larry Clark, Ph.D., and colleagues dropped an epidemiologic bombshell. In what many selenium researchers term "a landmark finding," Clark and his colleagues at the Arizona Cancer Center, Tuscon, found in a randomized trial for the prevention of skin cancers that people who supplemented their diets with bakers yeast rich in selenium reduced their overall risk of developing cancer by 40% (although there was no impact on risk of skin cancer) and reduced their risk of dying from cancer by nearly half, compared with the placebo group.
New Awareness
These dramatic results from the Nutritional Prevention of Cancer trial once again raised the important question: What exactly is it about selenium that tumor cells dont like? Find the answer, many scientists believed, and they would have an important mechanistic lead in learning how to prevent or control cancer.
In the early 1970s, researchers thought they had the answer in hand when they discovered selenocysteine, an amino acid that humans produce with selenium, stitched into glutathione peroxidase, a well-known antioxidant enzyme. The implication was that selenium played an important role in the bodys antioxidant defense system, where it helped to inactivate highly reactive oxygen free radicals.
But the antioxidant explanation proved simplistic. Scientists discovered in the 1980s that about two-thirds of the selenium in the rat binds to compounds other than glutathione peroxidase, providing strong evidence that the nutrient is broken down in the body into myriad metabolites, which, in turn, influence multiple biologic pathways.
"It is important to keep in mind that the biological activity of selenium is an expression of selenium in a wide variety of chemical compounds, and not the element per se," wrote Ganther at the time, a point highlighted by the fact that at least 15 different so-called "selenoproteins" have now been identified.
Enter DNA Repair
In this vein, Smith and his colleagues began 3 years ago to address the possibility that selenium could also induce DNA repair. If correct, because they would use doses of selenium that were nontoxic, the finding would suggest another possible chemopreventive strategy to prevent or control the abnormal growth of tumor cells.
"There was already some evidence, some hint in the literature, that selenium in the form of selenomethionine could activate p53," explained Smith, a molecular biologist. "So, we really wanted to take a closer look at it."
Smith noted that his laboratory was uniquely positioned to tackle the question. Not only had he and his group worked extensively on defining the DNA repair subpathway of p53a well-known regulator of this important cellular mechanismthey already had the in vitro tools up and running that would allow them to look specifically at where and how selenium affects the protein. Depending on the stimulus and the cell type, p53 can switch on various combinations of at least 100 human genes that are involved in either the DNA repair subpathway or apoptosis.
In the recent article, Smith and colleagues report that, although selenomethionine does not directly interact with p53, it does the next best thing. It activates a protein called Ref-1, which is known to reduce p53. That is, Ref-1 confers a partial negative charge on p53 that, like turning a key in an ignition, activates it.
Smiths group also reported that Ref-1 reduced p53 on one or possibly two specific cysteine amino acids. This suggested that these residues might be the specific molecular switches that transmit the Ref-1-generated signal further downstream, although the group did not directly demonstrate that these cysteines are plugged into the p53-mediated DNA repair subpathway.
The group did show that, after cells were exposed to selenomethionine, their p53 activity was threefold higher than at baseline. They also found that excision of base pairs, a sign of DNA repair, was increased by twofold. Interestingly, the scientists found no signs of cell cycle arrest or apoptosis, nor could they induce DNA repair in cell lines that were null for Ref-1 or p53, an indication that these proteins generated the signal.
How Much Is Enough?
For this study, Smith and colleagues exposed the cell lines to a selenium dose that they considered "within the physiological range of [previous chemoprevention] clinical studies." As the authors explained in the paper, "Cancer preventive use of selenium typically consists of 200 micrograms per day, exceeding the [recommended dietary allowances] by fourfold with no toxicity."
Others said they were less certain about this point. Refering to patients in the Nutritional Prevention of Cancer Trial, Ganther noted that even in patients who received high daily doses of selenal yeast (400 mg), their levels of selenium were only increased to about 3 micromolar, a standard measure of a compounds concentration in liquid. "Most people got half that dose, and the level was more on the order of 2 micromolar or less. So, when they (Smith and colleagues) used 20 micromolar, thats pushing it for interpretation."
Still, Ganther and others praised the study. "Even if repair isnt the mechanism, this is clearly something that theyve shown happens," said Douglas Brash, Ph.D., a scientist at Yale University who wrote a commentary on the paper in PNAS. "Certainly, it looks like the repair thing here is involved as a player."
If so, people who are naturally less adept at DNA repair might benefit from raising their dietary levels of selenium. As Brash noted in his commentary, the idea is not without precedent. Clinical studies with a topically applied DNA-repair-enhancing enzyme reduced precancerous skin lesions by one-third in people with xeroderma pigmentosum, a rare condition characterized by impaired DNA repair and predisposition to skin cancer.
Miles Away
As Brash and others also noted, the science is still miles away from this endpoint. One hurdle is that boosting ones intake of selenomethionine alone might accomplish little.
"The concentrations of the selenoproteins are homeostatically controlled and cannot be further increased above their maximum levels by additional selenium supply," noted Dietrich Behne, Ph.D., a scientist at the Hahn-Meitner-Institut in Berlin, Germany. "It is very unlikely that the chemopreventive effects of high doses of selenium are due to the actions of selenoenzymes." Behne added that the protective effects of the element may be caused by its other chemical forms and metabolites, such as methylated selenium.
Another hurdle is that the distribution of selenium varies from organ to organ. Studies in rats indicate that a hierarchy of selenium distribution exists in mammals, with the brain, spinal marrow, pituitary gland, and thyroid gland having first grabs at the element. This suggests that not all organs benefit equally from chemoprevention strategies with selenomethionine.
"You cant go from cell culture levels to dietary animal levels easily," noted Ganther. "Our group has shown that the same two compounds that have equal efficacy in animals in a cancer prevention study can have a tenfold difference in cell culture. An isolated, pure cell line does not have all of the equipment on board to necessarily to metabolize the percent of selenium to the active form."
However, as Smith noted, "It is hard to get at the mechanism in an animal. You really need a cell- and molecular-based system. I think it just takes time to put everything together."
Either way, Ganther said, "It is refreshing, isnt it, to have something besides the antioxidant action brought forth. I think this paper is going to stimulate a lot of discussion, and I think it is good to do that."
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