Selenium Biochemistry and Cancer:
A Review of the Literature

This section is compiled by Frank M. Painter, D.C.
Send all comments or additions to:    Frankp@chiro.org

FROM:   Alternative Medicine Review 2004 (Sep); 9 (3): 239-258 ~ FULL TEXT

Lyn Patrick, ND

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In recent years, the role of selenium in the prevention of a number of degenerative conditions including cancer, inflammatory diseases, thyroid function, cardiovascular disease, neurological diseases, aging, infertility, and infections, has been established by laboratory experiments, clinical trials, and epidemiological data. Most of the effects in these conditions are related to the function of selenium in antioxidant enzyme systems. Replenishing selenium in deficiency conditions appears to have immune-stimulating effects, particularly in patients undergoing chemotherapy. However, increasing the levels of selenoprotein antioxidant enzymes (glutathione peroxidase, thioredoxin reductase, etc.) appears to be only one of many ways in which selenium-based metabolites contribute to normal cellular growth and function. Animal data, epidemiological data, and intervention trials have shown a clear role for selenium compounds in both prevention of specific cancers and antitumorigenic effects in postinitiation phases of cancer.

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Introduction

Selenium’s unique role in human physiology has been found to include the prevention of atherosclerosis, specific cancers, arthritis, diseases of accelerated aging, central nervous system pathologies, male infertility, and altered immunological function. [1] Selenium is active in a variety of selenoproteins that include, but are not limited to, the glutathione reductases. [2] Other selenoproteins have roles that support immune function and, through specific cellular pathways, may play a preventive role in both the initiation and promotion of specific cancers. [3]

      Human Selenium Biochemistry

At least 25 selenoproteins have been identified in human biochemistry. The functions of selenium are believed to be carried out by selenoproteins, in which selenium is specifically incorporated as the amino acid selenocysteine. [2] In addition to incorporation as selenocysteine, selenium can replace sulfur in methionine, forming selenomethionine. This compound can be incorporated non-specifically into proteins in place of methionine. Finally, selenium can be tightly bound by certain proteins, known as selenium-binding proteins, to distinguish them from true selenoproteins. [2]

The first true selenoprotein identified was glutathione peroxidase, which catalyzes the oxidation of reduced glutathione and allows for the reduction of hydrogen peroxide to water, preventing lipid peroxidation and cellular damage. [4] There are basically five forms of glutathione peroxidase (GPx) that have been identified in human tissue: classical GPx (found only in the cell cytosol), gastrointestinal GPx (found in the liver and gastrointestinal tract), plasma glutathione peroxidase, phospholipid-hydroperoxide GPx (PHGPx), and sperm nuclei GPx.

Phospholipid-hydroperoxide GPx is found in cell nuclei, mitochondria, and the cytosol, and specifically acts to prevent lipid peroxidation in cell membranes. This is a unique function of this antioxidant enzyme, as most antioxidant enzymes cannot reduce phospholipid hydroperoxides inside cell membranes. [5] This particular form of GPx is found in high concentrations in spermatozoa, and is involved in sperm maturation and the prevention of cellular apoptosis. The ejaculate of infertile men contains significantly lower amounts of PHGPx compared to men with normal sperm counts and motility indexes. [6] As a class of enzymes, the PHGPx regulate eicosanoid production and cell signaling by reactive oxygen species. GPx levels in the blood and liver are responsive to early dietary selenium deficiency; whereas, the phospholipid-rich tissue membranes that contain PHGPx appear to be less affected by mild selenium deficiency. [6] Selenoprotein P, the majority of the selenium found in the bloodstream, also acts as an antioxidant enzyme and a selenium-transporter and appears to be very sensitive to dietary selenium. [7]

      Epidemiological Studies of Selenium and Cancer Risk

Erythrocyte, serum, plasma, and urine selenium levels have been found to be lower in a variety of cancer diagnoses compared to both matched and unmatched controls. [40-44] The majority of epidemiological studies also provide evidence for selenium as a chemopreventive agent for specific cancers: prostate, [45,46] lung, [47-49] colorectal, [50,51] stomach, [52] and multiple cancers. [42,53-54] The study of plasma selenium and non-melanoma skin cancers that led to the Nutritional Prevention of Cancer Trial, a 10-year prospective study of 1,738 Americans detailed below, found initial plasma selenium levels inversely correlated to both non-melanoma skin cancer and colonic adenomatous polyps. [55] Those with plasma levels below the U.S. population median of 128 ng/mL plasma were four times more likely to have one or more polyps than those with levels above 128 ng/mL.

In a prospective study of 39,268 men and women in Finland, risk for several cancers was significantly elevated in men who had the lowest level of serum selenium – for cancers of the stomach, pancreas, and lung specifically. [56] The mean levels of serum selenium found in those who developed cancer – 53-63 mcg/L – would be considered low in the United States. [57]

A prospective study of 4,857 Japanese patients followed serum selenium levels in those who developed cancers of all types over a 36-month period. [58] Those who developed cancer during the trial period had significantly lower serum selenium levels at baseline than those who were cancer free. Studies in China’s Qidong Province demonstrated a significant inverse association between the incidence of primary hepatocellular carcinoma and plasma selenium levels. [59] In an eight-year retrospective trial in Washington County, Maryland, those with low plasma selenium had a two-fold increased risk for bladder cancer. [60] A U.S. study of 11,000 hypertensives followed for five years showed a two-fold increase in risk for all cancers in those in the lowest (< 115 ng/mL) quintile compared to those in the highest quintile (> 154 ng/mL) of plasma selenium. [42]

A meta-analysis of large prospective studies has shown a consistent relationship between low prediagnostic levels of serum selenium in cancer patients compared to cancer-free controls. [61] The meta-analysis examined nine studies that assessed prediagnostic levels of antioxidants and 10 specific types of cancer. The levels of serum selenium in those who developed cancer of the stomach, pancreas, lung, and bladder were significantly lower than controls. The difference was most pronounced for pancreatic cancer.

Several studies have demonstrated no protective association between selenium and cancer risk. [62,63] Some studies that found no relationship between selenium and cancer risk used toenail selenium as a marker for selenium intake. [63] This method of assessing dietary selenium exposure and assuming toenail selenium as a reflection of tissue stores has been questioned by Schrauzer [64] when there is insufficient difference among quintiles of toenail selenium, raising concerns about toenail selenium being an imprecise tool in determining selenium status.

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