When hemolyzates from erythrocytes of selenium-deficient rats were incubated in vitro in the presence of ascorbate or H(2)O(2), added glutathione failed to protect the hemoglobin from oxidative damage. This occurred because the erythrocytes were practically devoid of glutathione-peroxidase activity. Extensively purified preparations of glutathione peroxidase contained a large part of the (75)Se of erythrocytes labeled in vivo. Many of the nutritional effects of selenium can be explained by its role in glutathione peroxidase.

Numerous studies in animal models and more recent studies in humans have demonstrated cancer chemopreventive effects with Se. There is extensive evidence that monomethylated forms of Se are critical metabolites for chemopreventive effects of Se. Induction of apoptosis in transformed cells is an important chemopreventive mechanism. Apoptosis can be triggered by micromolar levels of monomethylated forms of Se independent of DNA damage and in cells having a null p53 phenotype. Cell cycle protein kinase cdk2 and protein kinase C are strongly inhibited by various forms of Se. Inhibitory mechanisms involving modification of cysteine residues in proteins by Se have been proposed that involve formation of Se adducts of the selenotrisulfide (S-Se-S) or selenenylsulfide (S-Se) type or catalysis of disulfide formation. Selenium may facilitate reactions of protein cysteine residues by the transient formation of more reactive S-Se intermediates. A novel chemopreventive mechanism is proposed involving Se catalysis of reversible cysteine/disulfide transformations that occur in a number of redox-regulated proteins, including transcription factors. A time-limited activation mechanism for such proteins, with deactivation facilitated by Se, would allow normalization of critical cellular processes in the early stages of transformation. There is uncertainty at the present time regarding the role of selenoproteins in chemoprevention model systems where supranutritional levels of Se are employed. Mammalian thioredoxin reductase is one selenoprotein that shows increased activity with Se supplementation in the nutritional to supranutritional range. Enhanced thioredoxin reduction could have beneficial effects in oxidative stress, but possible adverse effects are considered. Other functions of thioredoxin reductase may be relevant to cell signaling pathways. The functional status of the thioredoxin/thioredoxin reductase system during in vivo chemoprevention with Se has not been established. Some in vitro studies have shown inhibitory effects of Se on the thioredoxin system correlated with growth inhibition by Se. A potential inactivating mechanism for thioredoxin reductase or other selenoenzymes involving formation of a stable diselenide form resistant to reduction is discussed. New aspects of Se biochemistry and possible functions of new selenoproteins in chemoprevention are described.

Japanese quail given 20 parts per million of mercury as methylmercury in diets containing 17 percent (by weight) tuna survived longer than quail given this concentration of methylmercury in a corn-soya diet. Tuna has a relatively high content of selenium and tends to accumulate additional selenium when mercury is present. A content of selenium in the diet comparable to that supplied by tuna decreased methylmercury toxicity in rats. Selenium in tuna, far from being a hazard in itself, may lessen the danger to man of mercury in tuna.

The compounds formed by the reaction of selenious acid with glutathione were studied with regard to the effects of pH and g1utathione:selenious acid ratio. At ratios of 4:l or less, and a pH below 2 and above 4, the first stable product is the selenotrisulfide derivative of glutathione (GSSeSG) plus an equimolar quantity of GSSG :GSSeSG free of GSSG was prepared by separating the two compounds on a Dowex 50 column equilibrated with 0.01 M NK12 in 0.1 h4 sodium acetate (pH 4.7) followed by adsorption of the GSSeSG fraction to Dowex 50 Naf at pH 3 and elution with ammonium acetate at pH 5.5. In order to determine the type of selenium compound formed under conditions more nearly simulating physiological conditions of pH and reactant concentrations, 75Se-labeled selenite (1 X 10+ M) was treated with 4 X M G S H at pH 7,25 O, followed by 50 mM iodoacetate. The major selenium compound thus formed was the Se-carboxymethyl derivative of glutathione selenopersulfide (GSSeH) ; this persulfide is believed to be formed by reduction of the initial selenotrisulfide product with excess GSH. Glutathione and elemental selenium were T he fate of selenious acid, or selenite, in systems containing thiols is relevant to many problems regarding the nutritional and toxicological aspects of this substance. Compounds of the type RSSeSR (2-selena-l,3-disulfides or seleno-This is the third paper in a series on selenotrisulfides. rapidly liberated from GSSeSG at pH 7 by 0.1 pg or less of highly purified glutathione reductase from yeast. The reduction of GSSeSG was not catalyzed by lipoyl dehydrogenase, nor was glutathione reductase active when DPNH or selenodicysteine (Cy SSeSCy) was substituted for TPNH or selenodiglutathione. The velocity of GSSeSG reduction was similar to that for GSSG reduction. Evidence was obtained that the initial reaction products were GSH and the selenopersulfide (GSSeH) : glutathione reductase + GSSeSG + TPNH + H+ GSH + GSSeH + TPN+The selenopersulfide rapidly decomposed lo GSH and elemental selenium but could be trapped in the presence of 50 mM iodoacetate as the carboxymethylated derivative, which was identified by thin-layer electrophoresis, thin-layer chromatography, and gel filtration. It is believed that this work provides the first evidence for the selenopersulfide class of compounds. These reactions may have important applications to selenium metabolism and the mechanism of action of selenium as an essential nutrient.trisulfides) have been shown in previous studies to be formed by the reaction of selenious acid with a variety of thiols (Ganther, 1968;Ganther and Corcoran, 1969) in accord with the equation first proposed by Painter (1941) 4RSH + H2Se03 + RSSeSR + RSSR + 3H20 (1)The most abundant thiol in biological systems is glulathione. A specific requirement for glutathione in selenite metabolism has been described (Ganther, 1966). The reaction of glutathione with selenious acid was indicated previously to be more complex than for other thiols (Ganther, 1968) and has now been studied in more detail. The...

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