The Role of Selenium in Human Metabolic Processes

Reference from the joint report of FAO/WHO expert consultation on Human Vitamins and Minerals verbatim.

1. Levander, O.A. 1986. Selenium. In: Trace elements in human and animal nutrition 5th edn. Mertz, W. ed. p 209-279. Orlando, Florida 209-279. Academic Press Inc. 

2. Arthur, J.R. & Beckett, G.J. 1994. Neometabolic roles for selenium. Proc. Nutr. Soc. 53: 615-624.

3. Ge, K. & Yang, G. 1993. The epidemiology of selenium deficiency in the etiological study of endemic diseases in China. Am. J. Clin. Nutr., Supplement 57: 259S-263S.

Our understanding of the significance of selenium in the nutrition of human subjects has grown rapidly during the past 20 years (1, 2). Demonstrations of its essentiality to rats and farm animals were followed by appreciation that the development of selenium-responsive diseases often reflected the distribution of geochemical variables which restricted the entry of the element from soils into food chains. Such findings were the stimulus to in-depth investigations of the regional relevance of selenium in human nutrition (3). 

These studies have now yielded an increased understanding of the complex metabolic role of this trace nutrient. Selenium has been implicated in the protection of body tissues against oxidative stress, maintenance of defences against infection, and modulation of growth and development. 

The selenium content of normal adult humans can vary widely. Values from 3 mg in New Zealanders to 14 mg in some Americans reflect the profound influence of the natural environment on the selenium contents of soils, crops, and human tissues. Approximately 30 percent of tissue selenium is contained in the liver, 15 percent in kidney, 30 percent in muscle, and 10 percent in blood plasma.

Much of tissue selenium is found in proteins as selenoanalogues of sulphur amino acids; other metabolically active forms include selenotrisulphidesand other acid-labile selenium compounds. At least 15 selenoproteins have now been characterised. Examples are given in Table 47.

 4. Arthur, J.R., Bermano, G., Mitchell, J.H. & Hesketh, J.E. 1996. Regulation of selenoprotein gene expression and thyroid hormone metabolism. Biochem. Soc. Trans.,

24: 384-388.

5. Howie, A.F., Arthur, J.R., Nicol, T., Walker, S.W., Beech, S.G. & Beckett, G.J. 1998.

Identification of a 57-kilodalton selenoprotein in human thyrocytes as thioredoxin

reductase. J. Clin. Endocrino.l Metab., 83: 2052-2058. 

Functionally, there appear to be at least two distinct families of selenium-containingenzymes. The first includes glutathione peroxidases (4) and thioredoxin reductase (5), whichare involved in controlling tissue concentrations of highly reactive oxygen-containingmetabolites. These metabolites are essential at low concentrations for maintaining cellmediatedimmunity against infections but highly toxic if produced in excess. The role ofselenium in the cytosolic enzyme glutathione peroxidase (GSHPx) was first illustrated in1973.

4. Arthur, J.R., Bermano, G., Mitchell, J.H. & Hesketh, J.E. 1996. Regulation of selenoprotein gene expression and thyroid hormone metabolism. Biochem. Soc. Trans., 24: 384-388.

5. Howie, A.F., Arthur, J.R., Nicol, T., Walker, S.W., Beech, S.G. & Beckett, G.J. 1998. Identification of a 57-kilodalton selenoprotein in human thyrocytes as thioredoxin reductase. J. Clin. Endocrino.l Metab., 83: 2052-2058. 

During stress, infection, or tissue injury, selenoenzymes may protect against the damaging effects of hydrogen peroxide or oxygen-rich free radicals. This family of enzymes catalyses the destruction of hydrogen peroxide or lipid hydroperoxides according to the following general reactions: 

where GSH is glutathione and GSSG is its oxidized form. At least four forms of GSHPx exist; they differ both in their tissue distribution and in their sensitivity to selenium depletion (4).

6. Mairrino, M., Thomas, J.P., Girotti, A.W. & Ursini, F. 1991. Reactivity of phospholipd hydroperoxide glutathione peroxidase with membrane and lipoprotein lipid hydroperoxides. Free. Radic. Res. Commun. 12: 131-135. 

The GSHPx enzymes of liver and blood plasma fall in activity rapidly at early stages of selenium deficiency. In contrast, a form of GSHPx associated specifically with phospholipid rich tissue membranes is preserved against selenium deficiency and is believed to have broader metabolic roles (e.g., in prostaglandin synthesis) (6). In concert with vitamin E, selenium is also involved in the protection of cell membranes against oxidative damage (see Chapter 6 (Vitamin C), Chapter 9 (Vitamin E), and Chapter 17 )Dietary Antioxidants). Note: Not yet posted.

5. Howie, A.F., Arthur, J.R., Nicol, T., Walker, S.W., Beech, S.G. & Beckett, G.J. 1998. Identification of a 57-kilodalton selenoprotein in human thyrocytes as thioredoxin reductase. J. Clin. Endocrino.l Metab., 83: 2052-2058.

6. Mairrino, M., Thomas, J.P., Girotti, A.W. & Ursini, F. 1991. Reactivity of phospholipd hydroperoxide glutathione peroxidase with membrane and lipoprotein lipid hydroperoxides. Free. Radic. Res. Commun. 12: 131-135.

The selenoenzyme thioredoxin reductase is involved in disposal of the products of oxidative metabolism (5). It contains two selenocysteine groups per molecule and is a major component of a redox system with a multiplicity of functions, among which is the capacity to degrade locally excessive and potentially toxic concentrations of peroxide and hydroperoxides likely to induce cell death and tissue atrophy (6).

7. Arthur, J. 1997. Selenium biochemistry and function. In: Trace Elements in Man and Animals - 9. Proceedings of the Ninth International Symposium on Trace Elements in Man and Animals. Fischer, P.W.F., L'Abbe, M.R., Cockell, K.A., Gibson, R.S. eds. p. 1-5.Ottawa, Canada, NRC Research Press. 

Another group of selenoproteins is essential in the conversion of thyroxin, or tetraiodothyronine (T4), to its physiologically active form, triiodothyronine (T3) (7). Three types of these iodothyronine deiodinases, differing both in tissue distribution and sensitivity to selenium deficiency, have been characterised.

The consequences of a low selenium status on physiologic responses to a shortage of iodine are complex. The influence of a loss of selenium-dependent iodothyronine deiodinase differs in its severity depending on whether a target tissue needs a preformed supply of T3 (e.g., via plasma) or whether, as with the brain, pituitary gland, and placenta, it can rely upon local synthesis of T3 from T4.

Despite this, marked changes in the T3-T4 ratio as a consequence of a reduced selenium status (when iodine supplies are also marginal) indicate the modifying influence of selenium on thyroid hormone balance in both animal models and human subjects. Their possible significance can be anticipated from the fact that whereas thyroid weights increase typically by 50 percent in rats offered an iodine-deficient diet, thyroid weight is increased 154 percent by diets concurrently deficient in both selenium and iodine.

8. Reilly, C. 1996. Selenium in food and health. London, Blackie Academic and Professional.

9. Anikina, L.V. 1992. Selenium-deficient cardiomyopathy (Keshan disease). In: Fifth International Symposium on Selenium in Biology and Medicine. Burk, R.F. ed. Vanderbilt University, Nashville, TN p 122.

Between 60 percent and 80 percent of selenium in human plasma is accounted for by a well-characterised fraction designated selenoprotein P, the function of which has yet to be determined. It is thought to be a selenium storage protein because there is limited evidence that it also has an antioxidant role. At least 10 other selenoproteins exist, including one which is a component of the mitochondrial capsule of sperm cells, damage to which may account for the development of sperm abnormalities during selenium deficiency. Other aspects of the function and metabolism of selenium are reviewed elsewhere (8, 9).