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.

https://science.sciencemag.org/content/sci/179/4073/588.full.pdf

Selenium: Biochemical Role as a Component of Glutathione Peroxidase

Oxidative mechanisms in the toxicity of metal ions

Levels of glutathione, glutathione reductase and glutathione S-transferase activities in rat lung and liver.

The glutathione S-transferases (GST) represent a major group of detoxification enzymes. All eukaryotic species possess multiple cytosolic and membrane-bound GST isoenzymes, each of which displays distinct catalytic as well as noncatalytic binding properties: the cytosolic enzymes are encoded by at least five distantly related gene families (designated class alpha, mu, pi, sigma, and theta GST), whereas the membrane-bound enzymes, microsomal GST and leukotriene C, synthetase, are encoded by single genes and both have arisen separately from the soluble GST. Evidence suggests that the level of expression of GST is a crucial factor in determining the sensitivity of cells to a broad spectrum of toxic chemicals. In this article the biochemical functions of GST are described to show how individual isoenzymes contribute to resistance to carcinogens, antitumor drugs, environmental pollutants, and products of oxidative stress.A description of the mechanisms of transcriptional and posttranscriptional regulat...

The glutathione S-transferase supergene family: regulation of GST and the contribution of the isoenzymes to cancer chemoprotection and drug resistance.

Aquatic chemistry is becoming both a rewarding and substantial area of inquiry and is drawing many prominent scientists to its fold. Its literature has changed from a compilation of compositional tables to studies of the chemical reactions occurring within the aquatic environments. But more than this is the recognition that human society in part is determining the nature of aquatic systems. Since rivers deliver to the world ocean most of its dissolved and particulate components, the interactions of these two sets of waters determine the vitality of our coastal waters. This significant vol ume provides not only an introduction to the dynamics of aquatic chem istries but also identifies those materials that jeopardize the resources of both the marine and fluvial domains. Its very title provides its emphasis but clearly not its breadth in considering natural processes. The book will be of great value to those environmental scientists who are dedicated to keeping the resources of the hydrosphere renewable. As the size of the world population becomes larger in the near future and as the uses of materials and energy show parallel increases, the rivers and oceans must be considered as a resource to accept some of the wastes of society. The ability of these waters and the sediments below them to accommodate wastes must be assessed continually. The key questions relate to the capacities of aqueous systems to carry one or more pollutants."

Metal pollution in the aquatic environment

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.

/pdf/selenium-metabolism-selenoproteins-and-mechanisms-of-cancer-2alc5s2kft.pdf

Selenium metabolism, selenoproteins and mechanisms of cancer prevention: complexities with thioredoxin reductase

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.

https://science.sciencemag.org/content/sci/175/4026/1122.full.pdf

Selenium: Relation to Decreased Toxicity of Methylmercury Added to Diets Containing Tuna

Previous research suggested that the β-lyase-mediated production of a
monomethylated selenium metabolite from Se-methylselenocysteine is a
key step in cancer chemoprevention by this agent. In an attempt to
affirm the concept, the present study was designed to evaluate the
activity of methylseleninic acid, a compound that represents a
simplified version of Se-methylselenocysteine without the amino acid
moiety, thereby obviating the need for β-lyase action. The in
vitro experiments showed that methylseleninic acid was more
potent than Se-methylselenocysteine in inhibiting cell accumulation and
inducing apoptosis in TM12 (wild-type p53) and TM2H (nonfunctional p53)
mouse mammary hyperplastic epithelial cells, and these effects were not
attributable to DNA damage, as determined by the comet assay. In
general, methylseleninic acid produced a more robust response at
one-tenth the concentration of Se-methylselenocysteine. It is possible
that these cell lines may have only a modest ability to generate a
monomethylated selenium species from Se-methylselenocysteine via theβ
-lyase enzyme. In contrast, methylseleninic acid already serves as a
preformed active monomethylated metabolite, and this could be an
underlying reason why methylseleninic acid acts more rapidly and exerts
a more powerful effect than Se-methylselenocysteine in
vitro . Interestingly, the distinction between these two
compounds disappeared in vivo, where their cancer
chemopreventive efficacies were found to be very similar to each other[
in both methylnitrosourea and
dimethylbenz( a )anthracene rat mammary tumor models].
The β-lyase enzyme is present in many tissues; thus, animals have an
ample capacity to metabolize Se-methylselenocysteine systemically.
Therefore, Se-methylselenocysteine would be expected to behave like
methylseleninic acid if β-lyase is no longer a limiting factor. Taken
together, the present in vitro and in
vivo results provide strong evidence in support of our earlier
hypothesis that a monomethylated selenium metabolite is important for
cancer chemoprevention. Methylseleninic acid could be an excellent
tool, especially for molecular mechanism studies in cell culture, and
some of these attributes are discussed.

https://cancerres.aacrjournals.org/content/canres/60/11/2882.full.pdf

Howard E. Ganther

Papers

Selenium: Biochemical Role as a Component of Glutathione Peroxidase

Selenium: Biochemical Role as a Component of Glutathione Peroxidase

Selenium metabolism, selenoproteins and mechanisms of cancer prevention: complexities with thioredoxin reductase

Selenium: Relation to Decreased Toxicity of Methylmercury Added to Diets Containing Tuna

In Vitro and in Vivo Studies of Methylseleninic Acid: Evidence That a Monomethylated Selenium Metabolite Is Critical for Cancer Chemoprevention