Higher Serum Selenium Levels and Vitamin E Supplementation

Selenium is an essential nutrient for humans; it fulfills the physiological requirements for more than 13 human enzymes and proteins. (1) Of the 40 nutrients currently recognized as essential for human nutrition, selenium was the last to be recognized in 1957. Its most well known function relates to the activation of the enzyme, glutathione peroxidase, which accounts for selenium’s antioxidant role in the reduction of hydrogen peroxide to water and organic hydroxyperoxides to alcohol. The form of selenium in all selenoproteins is an amino acid, L-selenocysteine. Both inorganic (e.g., selenite and selenate) and organic (seleno amino acids) forms of selenium have shown impressive cancer–chemopreventive effects in humans and in animal models. (2) This appears to be especially true for lung cancer, colorectal cancer and prostate cancer (3).

Except for skin cancer, prostate cancer is the most common type of cancer in men in the United States. In 2005, there were an estimated 232,090 new cases of prostate cancer and 30,350 deaths from this disease in the United States. Approximately 1 in 6 men in the United States (or 17.8 percent) will develop prostate cancer during his lifetime. All men are at risk, but those at highest risk fall into one or more of the following categories: age 55 or older; black; or have a father or brother with prostate cancer. (4)

A number of studies in recent years have suggested that selenium supplementation and/or higher serum levels of selenium may protect against prostate cancer.  For example, a study published in the December 2001 issue of The Journal of Urology found that low levels of serum selenium was associated with a 4 to 5 times increased risk of prostate cancer. The most recent evidence comes from the work of Dr. Ulrike Peters and colleagues of the Fred Hutchinson Cancer Research Center in Seattle. Their research, published in the American Journal of Clinical Nutrition in January 2007, showed a synergistic protective effect for higher serum levels of selenium coupled with vitamin E supplementation at or above 28 IU per day. The researchers used data from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial and tracked 724 incident prostate cancer case subjects and 879 control subjects over an eight-year period. The researchers compared selenium levels in blood samples collected before diagnosis from the subjects who developed prostate cancer, and from a comparison group of similar men who remained free of prostate cancer. Participants were also surveyed before entering the study for their dietary habits. Overall, those in the highest quartile of serum selenium (158-253 ng/ml) who reported daily vitamin E supplementation at or above 28 IU, experienced a 42 percent reduced risk of prostate cancer compared to those in the lowest. In regards to multivitamins, those in the highest quartile of selenium in their blood were 39 percent less likely to develop prostate cancer. Among smokers, higher serum selenium was also linked to a 35 percent reduced risk of prostate cancer. (5). Although researchers found that higher serum selenium levels, in the absence of vitamin E or multiple vitamin supplementation, did not appear to protect non smokers from prostate cancer, other intervention studies have shown a protective effect for selenium supplementation.

The Nutritional Prevention of Cancer Trial in the United States found a 65% reduction in prostate cancer incidence among those receiving selenium supplementation compared with those receiving a placebo.  The "Nutritional Prevention of Cancer Project" (NPC) was a controlled, randomized cancer prevention trial in which 1,312 patients received a daily dose of 200 mcg of selenium or a placebo for up to 10 years. There were 13 cases of prostate cancer in the treatment group compared to 35 cases in the placebo group during 7,818 person-years of follow-up. This was a statistically significant 63% reduction in the incidence of prostate cancer. (6,7)

It should also be noted that a meta-analysis of studies published since 1966 found a significant risk reduction in prostate cancer of about 30% in men with the highest dietary intake of selenium. (8).

The SELECT Trial Is Underway

The evidence to support the role of selenium and vitamin E as protective nutrients against cancer is strong enough for them to be chosen as interventions in the SELECT Trial. SELECT is the first study to look directly at the effects of selenium and vitamin E on the risk of prostate cancer. This study is designed to find out if selenium, vitamin E, or both prevent prostate cancer.

SELECT stands for the Selenium and Vitamin E Cancer Prevention Trial. The trial is funded by the National Cancer Institute (NCI) and is being coordinated by the Southwest Oncology Group (SWOG), an international network of research institutions that receives NCI funding. Enrollment began in 2001 and ended in 2004. The study will continue for 7 years after the last man enrolled, meaning that each man will participate for 7 years or more, depending on when he joined the study. More than 400 sites in the United States, Puerto Rico, and Canada are taking part in the study. Over 35,000 men are participating in SELECT.

The primary goal of SELECT is to assess the effect of these substances on the number of new cases of prostate cancer diagnosed during routine clinical practice. Other objectives are to assess the impact of selenium and vitamin E on the incidence of lung and colon cancer, as well as on survival. SELECT will also study the molecular genetics of cancer risk and associations between diet and cancer. Additionally, SELECT will examine quality of life.

The amount of vitamin E (provided as dl-alpha-tocopherol acetate) is 400 mg, which is roughly equivalent to 400 IU per day. However, it is thought that vitamin E at this dose may act as an anticoagulant and thus, men with uncontrolled high blood pressure were not eligible to take part in SELECT because taking this much vitamin E may increase their risk of stroke. Subjects were also provided with 200 mcg of daily selenium supplementation. Upon enrollment, men were asked to have toenail clippings collected to assess selenium levels in the body because selenium concentrates in fingernails and toenails. Toenails were chosen over fingernails because they take longer to grow and thus contain more history of someone’s selenium intake. Blood samples were collected upon enrolment to assess levels of vitamin E. Upon enrolling in the trial, men filled out a questionnaire regarding their dietary practices and past supplement use. There is also an annual questionnaire that asks for updates of some of this information. Men do not have to change their diets during this study. Participants are asked to return to the study site every 6 months to pick up a 6-month supply of capsules. (9).

Other Factors Related To Selenium’s Influence on Cancer

As a final note it should be noted that another recent study showed that selenium taken as oral supplementation accumulates preferentially in the human prostate gland as opposed to the seminal vesicles. The selenium concentration in prostate tissue was 22% higher in the group given the selenium. The authors conclude that these findings support the hypothesis that oral selenium supplementation may contribute to the cancer preventive effects of selenium in regards to prostate cancer (10).

In addition to selenium’s effect on activating antioxidant enzymes, such as glutathione peroxidase, experimental studies suggest that selenium provides other highly important anti-cancer benefits. At supraphysiological levels of intake, selenium has been shown to exhibit a number of anti-cancer properties.  These general mechanisms include:

• Apoptosis – programmed cell death of cancer cells
• Growth-inhibitory effects of cancer cells
• Induction of p53 tumour suppressor gene, which gives rise to proteins that arrest cell cycle division when DNA mutations occur, allowing DNA repair enzymes to correct the error.
• Protects against DNA damage
• Anti-promotional agent, discouraging cancer cell division.

The induction of apoptosis (a very important chemopreventive function) is detectable towards the upper limit of plasma selenium concentrations (approximately 5 micromoles per liter)

The present view is that selenium metabolites (i.e., methylated forms of selenium), rather than simply the saturation of L-selenocysteine synthesis alone, are key factors in selenium’s cancer preventive effects. (5) At physiological levels of intake, dietary selenium (inorganic and organic forms) is reduced to hydrogen selenide (H2 Se). From H2 Se, selenium is phosphorylated and incorporated into proteins such as L-selenocysteine.

During periods of supraphysiological intake (supplementation), once L-selenocysteine levels are saturated, H2 Se is rapidly methylated to dimethyl selenide and other methylated forms including the monomethylated form, and trimethylselenonium. Experimental studies highlight the fact that these methylated forms of selenium (metabolites) possess direct and indirect chemopreventive effects that are not attainable by the action of glutathione peroxidase acting alone.  As well, selenium has strong interactions with heavy metals such as cadmium, silver and mercury in marine foods and may protect against the toxic effects of these metals

Thus, selenium supplementation (100-400 mcg per day) increases the levels of methylated selenium metabolites that appear to account for many of selenium’s cancer preventive effects. (11,12,13,14)

As we await the results of the SELECT Trial, many health authorities have already instructed their patients to include daily selenium supplementation at 100-400 mcg per day, based on the current body of evidence to support its role in cancer prevention.

References:

1. Spallholz, J.E., et al. Dimethyldiselenide and methylseleninic Acid Generate Superoxide in an In Vitro Chemiluminescence Assay in the presence of Glutathione: Implications for the Anticarcinogenic Activity of l-Selenomethionine and L-Se-Methylselenocysteine.  Nutrition and Cancer : 40 (1); 34-41
2. Woo Youn, B., et al. Mechanisms of Organoselenium Compounds in Chemoprevention: Effects on Transcription Factor-DNA Binding. Nutrition and Cancer: 40 (1); 28-33)
3. Combs GF Jr; Clark LC; Turnbull BW.  Reduction of cancer risk with an oral supplement of selenium. Biomed Environ Sci.  1997 Sep;10(2-3):227-34.
4. American Cancer Society (2005). Cancer Facts and Figures 2005. Atlanta, GA: American Cancer Society. Retrieved May 24, 2005, from http://www.cancer.org/downloads/STT/CAFF2005f4PWSecured.pdf
5. Urlike P; Foster CB; Chatterjee N; Schatzkin A; Reding D; Andriole G.L. et al. Serum selenium and risk of prostate cancer – a nested case-control study. Am J Clin Nutr. 2007; 85:209-17.
6. Li, H., et al., A prospective study of plasma selenium levels and prostate cancer risk. J Natl Cancer Inst, 2004. 96(9): p. 696-703.
7. Duffield-Lillico, A.J., et al., Baseline characteristics and the effect of selenium supplementation on cancer incidence in a randomized clinical trial: a summary report of the Nutritional Prevention of Cancer Trial. Cancer Epidemiol Biomarkers Prev, 2002. 11(7): p. 630-9
8. Etminan, M., et al., Intake of selenium in the prevention of prostate cancer: a systematic review and meta-analysis. Cancer Causes Control, 2005. 16(9): p. 1125-31.
9. Selenium and Vitamin E Cancer Prevention Trial (SELECT): Questions and Answers http://www.cancer.gov/cancertopics/factsheet/Prevention/SELECT
10. Sabichi A.L. Selenium accumulation in prostate tissue during a randomized, controlled short-term trial of l-selenomethionine: a Southwest Oncology Group study. Clin Cancer Res, 2006;12(7 Part 1):2178-2184).
11. Fleming, J, et al. Molecular Mechanisms of Cancer Prevention by Selenium Compounds. Nutrition and Cancer: 40 (1); 42-49
12. Kim, Y.S., Milner, J. Molecular Targets for Selenium in Cancer Prevention. Nutrition and Cancer: 40 (1); 50-54
13. Combs, Jr., Gerald F. Impact of Selenium and Cancer-Prevention Findings on the Nutrition-Health Paradigm. Nutrition and Cancer: 40 (1); 6-11
14. Magos L & Webb M (1980): The interactions of selenium with cadmium and mercury. In Critical Reviews in Toxicology, ed. L Goldberg, pp 1?42. Cleveland, OH, USA: CRC Press.