P. D. Whanger

Selenium and its relationship to cancer: an update

Selenomethionine (Semet) is the major seleno-compound in cereal grains and enriched yeast whereas Se-methylselenocysteine (SeMCYS) is the major seleno-compound in Se-accumulator plants and some plants of economic importance such as garlic and broccoli exposed to excess Se. Animals can metabolize both Semet and SeMCYS. Epidemiological studies have indicated an inverse relationship between Se intake and the incidence of certain cancers. Blood or plasma levels of Se are usually lower in patients with cancer than those without this disorder, but inconsistent results have been found with toenail-Se values and the incidence of cancer. There have been eight trials with human subjects conducted on the influence of Se on cancer incidence or biomarkers, and except for one, all have shown a positive benefit of Se on cancer reduction or biomarkers of this disorder. This is consistent with about 100 small-animal studies where Se has been shown to reduce the incidence of tumours in most of these trials. Se-enriched yeast is the major form of Se used in trials with human subjects. In the mammary-tumour model, SeMCYS has been shown to be the most effective seleno-compound identified so far in reduction of tumours. Several mechanisms have been proposed on the mechanism whereby Se reduces tumours. Even though SeMCYS was shown to be the most effective seleno-compound in the reduction of mammary tumours, it may not be the most effective seleno-compound for reduction of colon tumours.

Selenocompounds in Plants and Animals and their Biological Significance

There are several selenocompounds in tissues of plants and animals. Selenate is the major inorganic selenocompound found in both animal and plant tissues. Selenocysteine is the predominant selenoamino acid in tissues when inorganic selenium is given to animals. Selenomethionine is the major selenocompound found initially in animals given this selenoamino acid, but is converted with time afterwards to selenocysteine. Selenomethionine is the major selenocompound in cereal grains, grassland legumes and soybeans. Selenomethionine can also be the major selenocompound in selenium enriched yeast, but the amount can vary markedly depending upon the growth conditions. Se-methylselenocysteine is the major selenocompound in selenium enriched plants such as garlic, onions, broccoli florets and sprouts, and wild leeks.

Biological function of metallothionein: I. Synthesis and degradation of rat liver metallothionein☆

Abstract The synthesis and degradation of rat liver metallothionein (MT) were investigated using 14C-cystine as precursor, Cd to stimulate the synthesis of this protein, and Sephadex G-75 chromatography as an isolation method. Incorporation of 14C-cystine into MT was normally low, but was greatly stimulated by s.c. Cd injection which also caused a temporary, but great, accumulation of Zn in MT fraction. A biological half-life of 4.2 days was found for liver MT. A second dose of Cd given after ip 14C-cystine injection prolonged only slightly the half-life (4.9 days). While Cd in the MT fraction remained at a constant level, Zn disappeared from this fraction at a rate similar to that of 14C-labeled MT, indicating the involvement of MT in Zn metabolism. This was further indicated by the stimulatory effect of s.c. Zn injection on the incorporation of 14C-cystine into MT. This stimulatory effect was also shared by s.c. injection of Cu and Hg. Further purification of MT fraction obtained by Sephadex G-75 chromatography on a DEAE-cellulose column revealed two MT peaks which contained more than 90% of the 14C, Cd and Zn put on the column, and high sulfhydryl groups ( 13.9 and 14.0-SH 10,000 MW , respectively). This verified that 14C-cystine was indeed incorporated into MT and that Sephadex G-75 chromatography was an adequate separation technique for isolation of MT for the present study.

Selenoprotein W of rat muscle binds glutathione and an unknown small molecular weight moiety

When purified from rat muscle, selenoprotein W is fractionated into four forms distinguished by slightly different chromatographic behavior. Precise masses of the four forms were determined by matrix-assisted laser desorption/ionization (MALDI) time-of-flight mass spectrometry. The mass distribution of the forms (9549, 9592, 9853, and 9898 d) suggests that they occur through derivatization of the lowest mass form with two moieties of approximate masses 44 and 305 d. The apparent 305 d moiety was demonstrated to be glutathione (307 d) by reductive release from the 9853 d protein form with 1000-fold excess of dithiothreitol at 50 degrees C. Milder conditions failed to remove the glutathione. The reduction produced nearly stoichiometric amounts of free glutathione as determined by HPLC of a fluorometric derivative. HPLC retention of the protein changed to match that of the 9549 d form, and a change of mass to 9550 d was observed by MALDI mass spectrometry. The identity of the 44 d moiety is unknown. The presence of glutathione in isolated selenoprotein W may suggest its involvement in the metabolism of this tripeptide.

Selenium - induced redistribution of cadmium binding to tissue proteins: a possible mechanism of protection against cadmium toxicity.

The mechanisms involved in the protection by Se against Cd toxicity in the rat were investigated. Se was found to significantly increase the Cd content in the blood and the testis, while decreasing that in the liver and kidney. Se diverted almost all the Cd in the soluble fraction of the testis from low-molecular-weight (MW) proteins to larger ones. Since the soluble fraction was the major subcellular Cd-binding component, the diversion of Cd by Se appears to be a mechanism involved in the protection by this element against the Cd-induced testicular injury. The diversion in binding of the Cd in the soluble fraction to higher MW proteins was also observed in the kidney and liver, and may be a second mechanism involved in the protection of these organs against Cd by Se, in addition to the reductive effect of Se on the tissue Cd concentration. Se was also found in these higher MW Cd-binding proteins. Based on a similarity of MW of about 115,000, the Cd-binding, Se-containing proteins found in these organs appear to be similar. A diversion of Cd from lower MW proteins to larger ones by Se was also found in the plasma, but the Cd-binding, Se-containing proteins in plasma appear to be different from those found in the other organs since they have a larger MW.

Tissue distribution and influence of selenium status on levels of selenoprotein W.

Rabbits were immunized with two synthetic peptides based on hydrophilic regions of selenoprotein W from rat muscle. The resulting polyclonal antibodies were used in Western blots to determine the compartmentation and tissue distribution of selenoprotein W, and to determine the influence of selenium on the levels of this selenoprotein in rat muscle. Selenoprotein W exists mainly in cytosol, but very small amounts were associated with membranes. Western blots revealed selenoprotein W in muscle, spleen, testis, and brain of rats. Rats were fed diets of either no addition of selenium (0 ppm Se) or additions of 0.1 and 4.0 mg selenium/g (0.1 ppm Se and 4.0 ppm Se) diet for 6 wk. Selenoprotein W was undetectable in skeletal muscle of rats fed the basal diet, detectable in those fed 0.1 ppm selenium in the diet, and much higher in muscle from rats fed 4 ppm selenium diet. In a species comparison, Western blots indicated the presence of selenoprotein W in muscle of rabbits, sheep, and cattle.—Yeh, J‐Y., Beilstein, M. A., Andrews, J. S., Whanger, P. D. Tissue distribution and influence of selenium status on levels of selenoprotein W. FASEB J. 9, 392–396 (1995)

Selenium and mercury interactions with emphasis on fish tissue.

This review addresses the effects of mercury (Hg) in fish as it relates to the health of the fish themselves as well as potential risks of toxicity in wildlife and humans that consume fish. In particular, it addresses selenium (Se) as a bioindicator of susceptibility to harmful effects of Hg exposures and evaluates how Se moderates the toxic effects of Hg in a variety of test animals, emphasizing the importance of these potential effects in fish. A major conclusion of this review is that Hg toxicity risks to animal life cannot be accurately assessed without considering the moderating effects of Se. Therefore, Se:Hg molar ratios and their mathematical inverse are important factors that need to be considered when assessing risks from Hg exposures because exposures are related directly to toxicity outcome. In addition, actual measurement of both beneficial nutrients (e.g., Se, omega-3 fatty acids) and contaminants (e.g., Hg, polychlorinated biphenyls [PCB]) in fish tissue, rather than gross associations betw...

SELENIUM PROTEINS IN OVINE TISSUES II. SPECTRAL PROpERTIES OF A 10,000 MOLECULAR WEIGHT SELENIUM PROTEIN.

Abstract A selenium-containing protein of 10,000 molecular weight, which is absent in muscle of selenium deficient lambs, was purified from the muscle extract of lambs injected with selenium. The absorption, circular dichroic, and magnetic circular dichroic spectra of the protein with and without dithionite markedly resemble the oxidized and reduced spectra reported for cytochrome C. Thus, this protein contains a heme group identical to cytochrome C, and may be a selenium containing cytochrome.

Uptake of selenite, selenomethionine and selenate by brush border membrane vesicles isolated from rat small intestine

The uptake of selenite, selenate and selenomethionine (SeMet) was performed with brush border membrane vesicles (BBMV) prepared from rats fed selenium-deficient and supplemented diets. At equilibrium (60 min), the uptake of 75Se from [75Se]selenite ranged from 16.5 to 18.9 nmol mg-1 protein. There was a curvilinear relationship in the uptake of selenite over a concentration range of 10–1000 μm. About 2 nmol mg-1 protein was obtained with selenomethionine (SeMet) which occurred between 90 and 180 s. In contrast to selenite, there was a linear relationship in the initial uptake of SeMet over a concentration range of 10–1000 μm. The uptake of selenate was approximately 50-fold lower than selenite, reaching 350 pmol mg-1 protein. Dietary selenium level had no effect on the rate of 75Se accumulation by BBMV. Dramatic differences are found in the uptake and binding of selenium by BBMV incubated with different selenocompounds.

Blood selenium and glutathione peroxidase activity of populations in New Zealand, Oregon, and South Dakota.

The relationship of whole blood selenium (Se) to glutathione peroxidase (GPX) activity was examined for individuals in New Zealand, Oregon, and South Dakota who represented, respectively, populations with exposure to low, medium, and high amounts of Se. The mean (respective) blood Se levels were 60, 200, and 400 ng/ml. Intergroup differences in blood Se levels were highly significant (P < 0.001). GPX assays were performed using two variations of an enzyme‐coupled procedure to assess the equivalence of the two methods. Despite a fourfold difference in absolute activities measured by these methods, the GPX activities were highly correlated (r = .86) between procedures. Average blood GPX activity was significantly lower (P < 0.001) for the New Zealand group compared with the other two groups, but there was no difference in GPX activities between the Oregon and South Dakota groups. Linear regression of GPX vs. Se values within each group indicated a significant correlation of these parameters only in the New Zealand group (r = .46, P < 0.01). Comparison of these parameters for combined data from all three groups also showed a significant positive correlation (r = .60, P < 0.001). A saturation model (ln GPX = k1+k2 (Se)−1] fits the combined data better (r = .80, P < 0.01) than does direct comparison of the two parameters. These results suggest that GPX activity is an appropriate indicator of human Se status only in populations with below normal exposure to Se, as activity of this enzyme is saturated at relatively low levels.—Whanger, P. D.; Beilstein, M. A.; Thomson, C. D.; Robinson, M. F.; Howe, M. Blood selenium and glutathione peroxidase activity of populations in New Zealand, Oregon, and South Dakota. FASEB J. 2: 2996‐3002; 1988.