Introduction to Selenium and its Biochemistry

First isolated in 1817 by J.J. Berzelius,1 selenium (Se) is a group 16 metalloid, lying directly below sulfur in the periodic table. Like sulfur, selenium may be found in the oxidation states of 0, —2 (selenide), +4 (selenite) and +6 (selen-ate).2 4 It is the 73rd most common element in the earth's crust,5 making it the least abundant element that has been shown to possess a defined role in human biology.4

The toxic effects of selenium had been reported as early as 1295. In China, Marco Polo described the symptoms of acute selenosis (blind staggers)4 that was suffered by livestock grazing on plants now known to be selenium accu-mulators.6 Despite this, selenium was shown to be an essential trace element in mammals in 19577 although it was 16 years before its roles in mammalian biology were defined.

It is now understood that a healthy human diet requires around 55-70 mg of selenium per day8 although as much as 10 times this amount may be ingested

Metallotherapeutic Drugs and Metal-Based Diagnostic Agents: The Use of Metals in Medicine Edited by Gielen and Tiekink © 2005 John Wiley & Sons, Ltd without ill-effect.9 A daily intake in excess of 900 mg per day has been shown to trigger the onset of chronic selenosis, the symptoms of which may include gastrointestinal upsets, hair loss, malformed nails and mild nerve damage.10,11

As its position on the periodic table suggests, selenium chemistry has a great deal in common with sulfur chemistry. This fact is exploited by living systems, which often use the same enzymes as those used for inorganic sulfur metabolism to metabolise inorganic selenium.6 Mammals reduce selenite to the key selenium metabolite selenide (H2Se) with the enzymes glutathione reductase or thioredoxin reductase (TrxR). Excess selenide may then be successively methylated to yield the volatile (and malodorous) methylselenol and dimethylselenide (Figure 17.1).12 These compounds are excreted through the lungs, leading to pungent breath in people with excessive selenium in their diets.4 Further methylation produces the trimethylselenonium ion, which is soluble in water and may be excreted in urine.12,13 These metabolic pathways enable the removal of excess selenium from the body.

The amino acid selenocysteine (SeCys) is the principal form by which mammals exploit selenium chemistry for biological activity,6,14 and its widespread presence across most living kingdoms has seen it dubbed the 21st amino acid.15 Birringer etal.6 provide an excellent discussion of selenium-containing metabolites and pathways in a recent review.

Figure 17.1 Pathways of selenium metabolism

The first defined role for selenium in mammals was in the enzyme glutathione peroxidase (GPx), which was described in 1973.16 The chief role of GPx is to catalyse the reduction of potentially harmful lipid peroxides to alcohols where glutathione is the reducing agent.17 Since this discovery, some 18 selenium-containing proteins have been detected in humans and the roles of many of them are the subject of much debate.6 Of those whose roles have been elucidated, GPx, TrxR18 and iodothyronine deiodoninases19 are among the best understood in terms of biological function. Mammalian TrxR is associated with a number of important reactions including the reduction of potentially harmful peroxides, disulfide bonds in peptides, regeneration of ascorbic acid (vitamin C) and the reduction of selenite to selenide.20 In all cases selenium is present in the form of SeCys.

Less well-understood selenoproteins include those with uninspiring names such as selenoprotein P and selenoprotein W. While most do not have universally accepted roles in biology, many are implicated in various processes. Selenoprotein P, for example, is an extraordinary water-soluble glycoprotein containing up to 12 SeCys residues.6 Several theories regarding its biological function have been postulated, including as a heavy-metal binding agent,21 blood-borne anti-oxidant,22 cell death inhibitory factor23 and an unusual form of selenium transport.24

This chapter aims to provide an insight into the therapeutic potential of natural and synthetic selenium-containing compounds that exhibit interesting and beneficial biological activity. It is beyond the scope of this chapter to cover all applications or therapeutics; however, we have selected some interesting examples to focus on. In addition, a number of excellent review papers are available (and cited where appropriate) for more in-depth critiques.

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