Biochemistry of Selenium Metabolism

EFFICACY OF VARIOUS FORMS

Although chemical characterization of the various natural states of selenium in foods and feeds has been hampered by analytical difficulties, it is apparent that this element is consumed by man and animals in several organic and inorganic forms. With the exception of indicator plants, which accumulate high concentrations of this element when grown on seleniferous soils, the selenium in crop and forage plants appears to be present mainly as an integral part of the proteins. On the other hand, selenium in avid accumulators, such as woody aster, is present predominantly as the soluble seleno amino acid analogs of cysteine and cystathionine. Because of its relative scarcity in soils and its active conversion to organic forms in plant tissue, selenite is usually a minor constituent of plants. The selenium associated with plant proteins is apparently present mainly in analogs of the common sulfur amino acids: selenocystine, selenocysteine, selenomethionine, and selenocystathionine.

Comparative assays have revealed a general similarity in the biological activity for animals of numerous inorganic and organic forms of selenium. The selenium in alfalfa and milk is similar in efficacy to selenite selenium in preventing exudative diathesis in chicks and liver necrosis in rats (Mathias et al., 1965, 1967). Selenic acid, selenate, selenium dioxide, selenite, and selenocyanate are of the same relative activity as selenocystine, selenocystathionine, selenomethionine, and various other organic selenides (Schwarz and Foltz, 1958). Elemental selenium is biologically inactive. Although certain organo-selenium compounds, such as di-seleno-7, 7:di-w-valeric acid and Factor 3 (an unidentified substance in various natural materials), have been reported to be more active than selenite in preventing liver necrosis, the margin of superiority is relatively small (Schwarz and Foltz, 1958). Research is continuing in comparing relative biopo-tencies of organoselenium compounds. Recent findings suggest a relationship between length and arrangement of the carbon chain and potency in protecting against liver necrosis for certain mono-and di-seleno dicarboxylic acids (Schwarz and Fredga, 1968). These findings are only empirical at present.

The fact that a variety of dissimilar organic and inorganic forms of selenium may possess similar biopotency presents a biochemical puzzle. How are these widely divergent organoselenium compounds converted with comparable efficiency to a common metabolically active form?

THEORIES ON SITE AND NATURE OF METABOLIC ACTIVITY

Seleno amino acids are actively incorporated into animal proteins, presumably by the same enzymic reactions that apply to their sulfur-containing counterparts. They also participate in various other metabolic reactions usually associated with their thio-analogs. For example, rat liver S-adenosyl methyltransferase uses selenomethionine as substrate in forming creatine and choline (Pan and Tarver, 1967). Selenium analogs of glutathione and coenzyme A have been reported in liver (Lam et al, 1961). Saccharomyces cerevisiae (Bremer and Natori, 1960) and Escherichia coli (Tuve and Williams, 1961) reportedly incorporate selenite selenium into seleno amino acids, whereas baker's yeast appears to lack this capacity (Tuve and Schwarz, 1961). There is little information on the metabolism of selenate by animals, but studies on plants have revealed important differences between the metabolism of sulfate and selenate, differences evidenced by an inability to form phosphoadenosine-5 1 phosphoselenate from adenosine-5 :phosphoselenate (Nissen and Benson, 1964).

Although there appears to be good evidence that inorganic selenium is incorporated into plant proteins, there are conflicting data relative to its utilization for the synthesis of selenoproteins in animal tissues. If the general analogy between sulfur and selenium metabolism applies, synthesis of seleno amino acids by animals would be contraindicated. However, evidence that inorganic 75Se is incorporated into liver proteins of the dog has been obtained by hydrolysis of the protein and paper chromatographic separation of the resulting amino acids (McConnell and Wabnitz, 1957). The radioactivity was mainly associated with cystine and methionine, and was attributed to the seleno analogs of these compounds. Similar experiments on rats yielded analogous results (Schoental, 1967). On the other hand, after labeled selenite was administered to rabbits, it was found that all the radioactivity could be removed from the liver protein by rigorously purifying the enzyme hydrolysate by dialysis and ion exchange (Cummins and Martin, 1967). The 75Se associated with cystine and methionine in the urine could also be removed by chromatography. In both instances the radioactivity was recovered as 75Se-selenite. It was concluded that the selenite ion is firmly bound to sulfur in vivo in a manner analogous to the binding observed in liver homogenates (Schwarz and Sweeney, 1964). In this connection, it has been shown (Ganther and Corcoran, 1969) that selenious acid combines with sulfhydryl compounds to form selenotrisulfides (RSSeSR); whether this is a significant reaction in vivo is unknown. This finding may account for the earlier reports of de novo synthesis of seleno amino acids.

Although the biosynthesis of seleno amino acids by rumen microorganisms in vivo has been reported (Rosenfeld, 1962), no incorporation of selenite selenium into amino acids was found in vitro under conditions that allowed incorporation of sulfate (Paulson et al., 1968a). Whether this discrepancy is due to differences in methodology or to binding of selenium to sulfur (Cummins and Martin,

1967) is unknown. If selenoproteins are synthesized by rumen microorganisms, it appears likely that the seleno amino acids released by digestion are utilized for protein synthesis in the tissues of the animal. L-Selenomethionine is actively absorbed by the intestine (McConnell and Cho, 1967) and is apparently convertible to seleno-cysteine and selenocystine (Awwad et al, 1967). 75Se-methionine is incorporated into egg white proteins (Ochoa-Solano and Gitler,

The kinetics of selenium turnover in sheep is not markedly differ ent after administration of 75Se-labeled selenite, selenomethionine, or selenocystine (Jacobsson, 1966a, b; Ehlig et al., 1967). The main pathway of selenium excretion by ruminants is fecal, although the urinary pathway predominates after large subcutaneous doses. The respiratory route is apparently less important than it is in nonrumi-nants. Sheep have been reported to exhale less than 3 percent of an injected dose of selenite, whereas up to 40 percent of a subtoxic dose was recovered within 10 hr in the expired air of rats (Jacobsson, 1966a; Ganther and Baumann, 1962). Nonruminants also differ from ruminants in excreting more selenium in the urine than in the feces when the selenium is given orally (Smith et al., 1937); however, tissue distribution patterns are similar to ruminants and nonruminants (Wright and Bell, 1966). The radioactivity decay curve observed after administration of 75Se-selenite to the rat has been interpreted as reflecting two first-order metabolic processes occurring at widely different rates, an indication that selenium is converted from a rapidly excreted to a slowly excreted form (Blincoe, 1960).

The trimethyl selenonium ion has been identified as a major product in the urine of selenite-treated rats (Byard, 1969; Palmer et al., 1969). The metabolic pathway of formation of this compound is not known.

INTERRELATIONSHIPS WITH SULFUR, VITAMIN E, AND OTHER DIETARY FACTORS

It is apparent that the metabolic role of selenium in animals is linked with that of vitamin E and sulfur amino acids. Some diseases associated with low concentrations of selenium in the diet (less than 0.1 ppm) are analogous to those of vitamin E deficiency and are usually manifested under conditions of low intake of vitamin E. In some instances these syndromes have been observed to respond fully to administration of vitamin E; in others selenium was substantially more effective or induced a further response. For example, white muscle disease in lambs is readily prevented by administering selenium to the ewe, whereas vitamin E is essentially ineffective (Muth et al., 1958). Limited placental transfer of vitamin E evidently is one factor in this difference in efficacy, since the vitamin is active when given in therapeutic doses to lambs directly (Oldfield et al., 1960). Selenium is not only more efficiently transferred across the placenta and secreted in the milk but is also more actively retained in the tissues of the young. There are inconsistent reports that administration of selenium induces increased growth in lambs receiving adequate vitamin E (Ewan et al., 1968a). On the other hand, selenium is ineffective against other aspects of this syndrome, notably the susceptibility of the erythrocytes to hemolysis. Maximal overall response appears to depend on the presence of adequate amounts of both nutrients.

It is well established that the classic experimental deficiency diseases of vitamin E, such as resorption gestation in rats and muscular dystrophy in rabbits, cannot be prevented by dietary selenium (Draper, 1957; Machlin et al., 1959). Since these diseases can be prevented by certain synthetic antioxidants, it follows that if selenium functions as an antioxidant in vivo, its biological versatility in this respect is relatively limited. At the same time, there is extensive evidence that, although selenium cannot replace vitamin E in nutrition, it reduces the amount of tocopherol required and delays the onset of symptoms of deficiency.

Evidence that vitamin E functions in biological systems as a lipid soluble antioxidant, and the fact that it ameliorates in many instances the symptoms of selenium deficiency, prompted the proposal that selenium is converted in vivo into an organic compound, or into several compounds, with antioxidant properties. Administration of selenium to animals deficient in vitamin E reduces lipid peroxidation and increases antioxidant activity in the tissues (Bieri, 1959; Hamilton and Tappel, 1963). The synthetic antioxidant N, AT'-diphenyl-p-phenylenediamine (DPPD) is highly active in preventing "respiratory decline" (an incipient sign of liver necrosis) when administered intraportally to rats deficient in selenium and vitamin E (Mertz and Schwarz, 1958). Certain synthetic antioxidants are also capable of preventing exudates in chicks, although they are significantly lower in efficacy than vitamin E (Machlin et al., 1959). Selenium reduces the toxicity of CC14, an agent that catalyzes lipid peroxidation (Fodor and Kemeny, 1965). Selenomethionine is an active lipid antioxidant in vitro (Olcott et al, 1961) and is capable of decomposing lipid peroxides (Tappel, 1965). Seleno amino acids catalyze peroxide decomposition considerably faster than their sulfur analogs, and it has been calculated that on a molar basis seleno-proteins may have 50 to 100 times the antioxidant activity of vitamin E (Tappel, 1965). Seleno amino acids also protect proteins from radiation damage (Shimazu and Tappel, 1964). It has been proposed that seleno-proteins, functioning as antioxidants, are the active forms of selenium in vivo (Hamilton and Tappel, 1963). How ever, the view that selenium is incorporated into seleno amino acids in animal tissues has since been seriously challenged, and it now appears that this element cannot be completely replaced in the diet by vitamin E or other antioxidants.

At least a partial explanation of the relationship between selenium and vitamin E is suggested by experiments on exudative diathesis in chicks. Like liver necrosis in rats, this disease has been induced by feeding a diet low in selenium, vitamin E, and protein (sulfur amino acids). It has been a general observation that these diseases can be prevented by administering either selenium or vitamin E. However, experiments indicate that when chicks are fed a diet extremely low in selenium (<0.005 ppm), vitamin E no longer prevents kidney degeneration and mortality even when given in high concentrations (Thompson and Scott, 1968a). Exudates occur only after the body stores of vitamin E have become depleted as a result of poor absorption of the vitamin under these conditions. Evidence also was obtained that under these conditions the intestinal absorption of dietary lipids, including vitamin E, is severely inhibited. These observations suggest that selenium functions in the absorption of dietary vitamin E, affording a possible explanation of several other findings reported in the literature:

  • Selenium is active against exudates and muscular dystrophy in chicks only if some vitamin E is present in the diet (Calvert et al, 1962; Bieri, 1964).
  • Vitamin E levels in the tissues of rats are depressed by feeding a diet low in selenium (Witting et al, 1967).
  • Vitamin E is effective per se against respiratory decline when the liver is perfused with this compound in situ (Mertz and Schwarz, 1958).
  • Certain synthetic antioxidants that are capable under most circumstances of preventing a simple vitamin E deficiency are also capable of preventing respiratory decline (Mertz and Schwarz, 1958) and exudative diathesis (Fodor and Kemeny, 1965), caused by a combined deficiency of vitamin E and selenium.

The finding that in acute deficiency of selenium in chicks the absorption of both vitamin E and dietary triglyceride is impaired (Thompson and Scott, 1969) adds greatly to the metabolic significance of this element. Evidence has been obtained that in deficient chicks there is a reduction in pancreatic lipase activity and in lipid micelle formation in the lumen of the intestine. These phenomena appear to be the sequelae of a pathology of the pancreas. Addition of sodium taurocholate to the deficient diet increased absorption of vitamin E but did not prevent mortality from pancreatic degeneration (Thompson and Scott, 1970). This finding implies that selenium has some function in relation to the disease apart from its apparent role in facilitating absorption of vitamin E. In pregnant rats selenium has been found to decrease placental transfer of vitamin E to the fetus, possibly by enhancing its retention in the maternal tissues (Cheeke et al., 1969).

Sulfur amino acids protect against several diseases associated with low intakes of selenium and vitamin E. In some cases the protection appears to be partly attributable to contamination with selenium; in others it is apparent that these compounds are active per se. Myopathy in chicks occurs only when the diet is limiting in methionine or cystine or both (Dam et al, 1952; Scott and Calvert, 1962). Selenium is only partly protective against this disease, and synthetic antioxidants are less active than tocopherol (Machlin et al, 1959). Cystine delays the development of liver necrosis in rats fed diets low in selenium and vitamin E (Schwarz, 1965a). In contrast, sulfur amino acids do not appear to prevent the development of muscular dystrophy in lambs (Erwin et al, 1961) or turkey poults. In general, it may be concluded that sulfur amino acids moderate the effects of feeding diets deficient in these nutrients but cannot substitute for them. The only suggestion that has been offered to explain the efficacy of these amino acids is that they contribute to the antioxidant activity of the tissues. This theory is based on their known antioxidant activity in vitro and the observation that synthetic antioxidants are capable of replacing them as protective agents.

Although there is a general analogy between the organic and inorganic forms of selenium and sulfur that occur in the diets of animals, as well as in their known metabolic pathways, there is a marked difference between the two analogous series with respect to their efficacy in preventing diseases associated with a low intake of selenium. Whereas exudative diathesis, necrotic liver degeneration, and white muscle disease can be prevented by trace quantities of either organic or inorganic forms of selenium (e.g., 1.0 ppm), the same quantities of sulfur analogs exhibit little or no activity. It is evident, therefore, that selenium has some function in animal tissues that is performed with markedly less efficiency, if at all, by sulfur.

A number of attempts have been made to characterize the bio chemical changes that occur in the tissues of animals fed diets low in selenium. The respiratory cycle has been the main object of investigation because of the impaired respiration observed in prenecrotic liver tissue of rats deficient in both selenium and vitamin E. This inhibition is not seen in animals deprived only of vitamin E. These studies have indicated that the initial impairment involves, not oxidative phosphorylation or the electron transport system, but the dehydrogenases of the tricarboxylic acid cycle. In some studies the oxidation of succinate and isocitrate was found to be depressed, and it was proposed that lipoyl dehydrogenase is the site of inhibition (Schwarz, 1965a). There is no indication, however, that selenium is a cofactor for this enzyme. It may be theorized that selenium in some way (possibly mediated by its influence on vitamin E metabolism) maintains the enzyme in a reduced sulfhydryl state. Other investigators have proposed pyruvate rather than succinate oxidation as the site of respiratory inhibition (Bull and Oldfield, 1967). There is evidence that both selenium and vitamin E are necessary for the oxidation of pyruvate in liver homogenates of the rat and that neither substance is replaceable by synthetic antioxidants. Distribution studies (Wright and Bell, 1964, 1966) have shown that in instances of selenium deficiency, increased amounts of available 75Se are concentrated in the liver microsomal fraction. This finding suggests an involvement of selenium in the biochemical reactions related to ribonucleic acids, such as the biosynthesis of protein, or to enzymes localized in the endoplasmic reticulum. Among the latter are reactions related to the biosynthesis of steroids, phospholipids, and mucopolysaccharides as well as cytochrome-linked enzymes. An explanation of these various findings probably will require detailed studies utilizing purified enzymes.

There are some indications of metabolic interrelationships between selenium and other microelements. Comprehensive trials with Romney ewe lambs in New Zealand (Hill et al, 1969) showed that live weight, fleece weight, and fecundity responses could be induced by copper therapy, but only in animals that also received selenium. Clinical signs of selenium or copper deficiency were not observed in either the experimental ewes or their progeny during the trial, nor was the live-weight response visually notable; however, the significance of the differences in treatment emphasized the economic impact of deficiencies in marginal trace elements in sheep.

Gardiner and Nairn (1969) have studied the effects of selenium and cobalt in relation to estrogen-induced low fertility in ewes graz ing subterranean clover pasture in Australia. Reproductive performance was significantly lowered when excess cobalt was given (via 3 to 6 cobalt "bullets" in the rumen) to ewes grazing the estrogenic forage. Some evidence suggested that providing selenium tended to reduce, to some extent, the adverse effects of cobalt, but the nature of the metabolic interrelationship remains speculative. Wise et al. (1968) investigated relative tissue concentrations of cobalt and selenium in lambs fed a selenium-deficient diet and found low cobalt as well as selenium in the kidneys of animals showing signs of white muscle disease.

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