Selenium Supplementation and the Prevention of Colon Cancer

By James P. Meschino, DC, MS

Selenium, an essential nutrient for humans, fulfills the physiological requirements for more than 13 human enzymes and proteins.¹ 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 the 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

The nutritional requirement for selenium for the synthesis of L-selenocysteine is considered to be 55 micrograms per day. However, selenium consumed as a dietary supplement beyond levels attainable from food (i.e., up to 200 mcgs per day) is associated with reduced incidence of lung, colorectal and prostate cancer in humans. Animal studies also strongly indicate that supraphysiological levels of selenium significantly reduce cancer incidence in various test models.¹

Many cancer researchers now propose that the level of selenium required to reduce cancer risk exceeds the intake level (55 mcgs), upon which the RDA is based. At supraphysiological levels, selenium has been shown to exhibit a number of anti-cancer properties beyond the activation of the antioxidant enzyme, glutathione peroxidase. These general mechanisms include:

1. apoptosis-programmed cell death of cancer cells;


2. growth-inhibitory effects of cancer cells;


3. induction of p53 tumor suppressor gene, which gives rise to proteins that arrest cell cycle division when DNA mutations occur, allowing DNA repair enzymes to correct the error;


4. protection against DNA damage;


5. an anti-promotional agent, discouraging cancer cell division; and


6. the induction of apoptosis (a very important chemopreventive function), detectable toward the upper limit of plasma selenium concentrations (approximately five micromoles per liter).^3,4,5

The present view is that selenium metabolites (i.e., methylated forms of selenium), rather than simply the saturation of L-selenocysteine synthesis alone, is a key factor in selenium's cancer-preventive effects.⁵ At physiological levels of intake, dietary selenium (inorganic and organic) is reduced to hydrogen selenide (H₂Se). From H₂Se, selenium is phosphorylated and incorporated into proteins such as L-selenocysteine.

During periods of supraphysiological intake (supplementation), once L-selenocysteine levels are saturated, H2Se is rapidly methylated to dimethyl selenide and other methylated forms, including the monomethylated and trimethylselenonium forms. Experimental studies highlight 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. 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.^1,5

Note that under toxic conditions, this methylation metabolic pathway becomes rate-limiting, and dimethyl selenide is eliminated by pulmonary excretion, giving rise to garlic breath.¹

As reported by Combs, et al, selenium plasma levels of approximately 120 ng/ml (1.5 umol/ml) may be optimal for cancer prevention in general. The most recent estimates suggest that women require a minimum of 96 micrograms per day; men require at least 120 micrograms per day to support plasma levels at 120 ug/ml. These levels are 175 and 218 percent, respectively, of the revised RDA.⁶

In terms of specific cancers that may be prevented through selenium supplementation, colorectal cancer has received much attention in human and animal studies, and is the focus of this review.³

Diet and Colon Cancer

In North America, colon cancer is the second leading cause of cancer death after lung cancer. Cancer researchers Doll and Peto suggest that up to 90 percent of colon cancer in this part of the world may be avoidable by altering the diet. Less than five percent of all colon and rectal cancers can be attributed to known causes, such as family history, colon polyps that run in families (familial polyposis) or as a sequel to inflammatory bowel diseases, such or ulcerative colitis. Thus, colon and rectal cancers are considered to be preventable in the vast majority of cases. The 90-percent variation rate in colon and rectal cancers that exists among countries is considered to be largely due to specific dietary factors.⁷ In the U.S., 137,000 new cases and 57,000 deaths from large bowel cancer were expected in 2000.³

The body of evidence is highly suggestive that a high-fat, low-fiber diet increases the risk of colon cancer, whereas a low-fat, high-fiber diet tends to decrease the risk. In particular, wheat bran fiber has demonstrated important protective features as an anti-colon cancer agent. Studies also link higher intakes of vitamins E, C and calcium with a lower incidence of colon cancer. As well, low blood levels of beta-carotene are consistently associated with an increased risk of developing colon cancer.^{8,9,10,11,12,13,14,15,16}

A lesser-appreciated fact among health professionals is the extensive research that suggests selenium may be a highly protective micronutrient in the prevention of colon and rectal cancers.

Animal and Human Studies Using Selenium

Selenium is an essential trace mineral found in soils and crops, and has been shown to prevent chemically induced colorectal cancer in animals.

In one study, rats were fed an agent known to cause colon cancer. The rats whose diets were supplemented with selenium had a tumor incidence of only three percent, whereas the rats that received no selenium supplementation had a 29 percent tumor incidence.

Other animal studies have shown that selenium supplementation reduces the incidence of intestinal tumors by 50 percent, compared with rats given the cancer-causing agent without selenium supplementation.^17,18,19,20

Human observation studies are equally impressive. For example, areas with low soil and crop selenium content have higher rates for colon and rectal cancers. Other studies demonstrate that lower blood levels of selenium are associated with an increased risk of developing colon cancer.^{21,22,23,24,25}

In a study of U.S. veterans, blood levels of selenium were measured in subjects with colorectal cancer and those free from colon cancer. The results demonstrated that subjects with blood selenium levels below 128 micrograms per liter were 4.2 times more likely to have one or more cancerous polyps.²²

In a clinical trial using selenium to reduce risk of skin cancer, 1,312 subjects were given either 200 micrograms of selenium or a placebo. Although selenium was not found to be protective against skin cancer, subjects taking the selenium experienced a 58-percent reduction in colon and rectal cancers compared with subjects taking the placebo pill.²⁴

More recently, a study by Dr. Mark Russo and associates at the University of North Carolina further supported a role for selenium in the prevention of colon and rectal cancers. In their study, patients who were referred for a colonoscopy assessment also had blood tests. As reported by these authors, lower blood levels of selenium were associated with multiple cancerous lessons in the colon. The average blood level for patients with cancerous lessons was 107 micrograms per liter vs. 120 micrograms per liter for the cancer-free subjects.²⁵

The authors conclude that this data support a protective effect of selenium against colon and rectal cancers after adjustments for possible confounding factors such as smoking; use of dandruff shampoo (which contains selenium); alcohol; vitamin E; vitamin C; iron; fat; and fiber. "Our results demonstrate that individuals with high plasma (blood) selenium levels are at a decreased risk for colorectal adenomas (cancerous lesions)". An increase of 30 micrograms per liter in blood selenium level was associated with a 50-percent reduction in risk of colon cancer lesions.²⁵

The Protective Effect of Selenium

As noted, there are several ways that selenium is thought to reduce cancer risk. Selenium enhances antioxidant defenses by increasing activity and levels of the powerful antioxidant enzyme known as glutathione peroxidase, considered a strong anticancer agent.

Selenium supplementation also decreases the formation of certain cancer-permissive eicosanoids of the prostaglandin E2 series. Prostaglandin E2 has been shown to increase the rate of cell division of various cancer cells. Animal studies have demonstrated these effects quite extensively.

Selenium metabolism itself may initiate changes that lead to programmed cell death of cancer cells and precancerous cells.^26,27,31,32 It is important to note that human studies by Drs. Willett and Salonen also reported a two and threefold increased risk for colon and intestinal cancer, respectively, in patients presenting with low blood selenium levels, compared to patients with higher blood levels of selenium.^28,29 In line with these observations is the emerging evidence that selenium metabolites (methylated forms) exert a broad range of anti-cancer influences on the cell, including colonic epithelial cells, and that higher levels of selenium intake are required to produce protective levels of these methylated selenium compounds.^3,4,5

Current Trends and Practical Application

The average intake of selenium from food sources is shown to be between 50-70 micrograms daily. Is it adequate? The evidence suggesting that selenium can reduce the risk of certain cancers indicates that ingesting additional selenium from a supplement may be a prudent strategy. Many health-conscious physicians now recommend a daily supplement of 50-200 micrograms of selenium as part of a preventative health strategy.^30,33

As for safety, toxicity of selenium starting at doses of 1,000 micrograms per day, but doses as high as 2,000 mcgs per day have been shown to be nontoxic in some individuals.^6,30,33,34 Most clinical applications have used 100-500 mcg of selenium per day.^{28, 34}

Ingesting a safe level of selenium from a vitamin and mineral supplement may have other health benefits. For instance, the National Research Council stated that in animal studies: "A large accumulation of evidence indicates that supplementation of the diet or drinking water with selenium protects against tumors induced by a wide variety of chemical carcinogens." Significant protection was demonstrated against the development of breast, colon, liver, and skin cancers.³⁵

In humans, epidemiological studies have linked lower selenium intake to a higher incidence of leukemia, and cancers of the colon; rectum; pancreas; breast; ovary; prostate; bladder; skin; and (in the male) lung.³⁶ As a result of these studies, a number of clinical trials are underway testing selenium as a cancer preventive agent. In the Linxian, China study, the combination of selenium, vitamin E and beta-carotene was shown to reduce the incidence of stomach and esophageal cancers by 16 and 17 percent, respectively, in a very high-risk population.³⁷

Studies using selenium have also suggested that it plays a role in strengthening the immune system, reducing inflammatory conditions and reducing risk of heart disease and stroke.^38,39,40

In conclusion, selenium demonstrates very promising chemopreventive capabilities as reported in a number of animal and human studies. At recommended, supplemental doses (100-500 micrograms per day), it is extremely nontoxic. Moreover, it appears that selenium supplementation may be the only viable means to provide sufficient concentrations to enable the body to generate protective levels of methylated selenium metabolites, which are now considered important bioactive agents that account for much of selenium's anti-cancer effects.

It may be prudent to initiate a selenium supplementation early in life. As a rule of thumb, selenium supplementation at 1.5 micrograms per pound of body weight is reported to be a safe level that can be applied to children and young adults.³⁴ The best food sources of selenium include wheat germ; oats; whole wheat bread; bran; tuna; swordfish; oysters; turnips; barley; garlic; brown rice; and red Swiss chard.^30,34

As cancer of the colon and rectum now affects one in 20 people in the population at some point in their lifetime, using proactive nutrition and supplementation strategies to defend against this disease should be encouraged by primary health care professionals.

In addition to a low-fat, high-fiber diet, the body of evidence is highly suggestive that certain micronutrients, including vitamins C, E and D; beta-carotene; calcium; and selenium exert significant chemopreventive effects for colon and rectal cancers. As a matter of public health policy, health practitioners should be engaged in educating patients on the much-underrated relationship between nutrition and cancer. This is especially true in regards to colorectal cancers, as up to 90 percent of these cases are considered to be preventable through better nutrition and lifestyle practices.

References

 

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3. El-Bayoumy K, et al. Multiorgan sensitivity to anticarcinogenesis by the organoselenium 1, 4-phenylenebis (methylene) selenocyanate. Nutrition and Cancer 40(1);18-27.
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24. Clark L, Combs GF Jr, Turnbull BW, Slate EH, Chalker DK, et al. Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. JAMA 1996:276:1957-1964.
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37. Clot WJ, et al. The Linxian trials: mortality rates by vitamin-mineral intervention group. Am J Clin Nutr. 1995;62(suppl):14245-14265.
38. Kiremidjian-Schumacher L, et al. Supplementation with selenium and human immune cell functions, II, effect on cytotoxic lymphocytes and natural killer cells Bio Trace Elem Res 1994:41:103-114.
39. Tarp U, et al. Selenium treatment in rheumatoid arthritis. Scard J Rheumatol 1985;14:364-368.
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James Meschino,DC,MS
Toronto, Ontario
Canada
www.renaisante.com

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