Kenneth P. McConnell

Periodate-oxidized adenosine inhibits the formation of dimethylselenide and trimethylselenonium ion in mice treated with selenite.

The metabolic detoxification of selenite and many other selenium compounds involves a series of S-adenosylmethionine-dependent methylations yielding dimethylselenide (DMSe), which is exhaled, and trimethylselenonium ion (TMSe), which is excreted in the urine. This paper shows that periodate-oxidized adenosine (Adox) inhibits these methylation reactions in vivo and increases the toxicity of selenite. When Adox was injected in mice at 100 mumol/kg 30 min before injection of [75Se]selenite at 0.4 mg Se/kg the appearances of [75Se]DMSe in the breath and [75Se]TMSe in the liver were completely inhibited for 90 min. This was mediated by accumulation of S-adenosylhomocysteine, the methyltransferase inhibitor, in the livers of Adox-treated mice due to inhibition of its hydrolase enzyme. During 24 h, Adox-treated mice excreted no detectable urinary [75Se]TMSe and exhaled only 20% as much [75Se]DMSe as controls. The urine of Adox-treated mice also contained S-adenosylhomocysteine at a level (ca. 4 mM), 200 times that of untreated mice, which provided a convenient index of methylation potential in the intact animal. When three groups of three mice each were injected with 100 mumol Adox/kg, selenite at 4 mg Se/kg, or a combination of the two, the mice receiving the combination were dead within 2 days, while the mice in the other two groups all survived at least 4 days. These results verify the enzymatic nature of selenium methylation in vivo, support its importance in detoxification, and indicate the value of Adox in further studies of selenium metabolism.

Respiratory excretion of selenium.

Summary and conclusions The current experiments demonstrate that the formation and excretion of volatile selenium compounds occur soon after administration of 75SeO3= and L-seleno-75 methionine. The rate of excretion of volatile substances through the lungs when administered either as inorganic (75SeO3=) or organic (L-seleno-75 methionine) selenium is more rapid during the first 6 hours than during any subsequent 6-hour period up to 24 hours. On the basis of mg selenium per kg body weight, larger amounts of selenium are excreted when administered as inorganic than as organic selenium. It is apparent that the mechanism of methylation and rapid excretion via the respiratory gases assumes a more significant detoxification role when amounts of selenium approaching the lethal levels are administered.

Serum selenium and reticuloendothelial tumors.

Serum selenium levels were determined by neutron activation analysis on 59 patients with a variety of reticuloendothelial neoplasms. Correlations were attempted between the widely variable range in the serum concentrations of the trace element with the parameters employed in this study. Therapy, particularly less than six weeks initiation, produced elevations in the serum selenium levels.

Interrelationship between selenium and specific trace elements.

Conclusion The pattern in the distribution and excretion of selenium in the presence of other trace elements varied from one trace element to the other and with the mode of injection. The precise mechanism by which Te6+, As5+, Cd2+, or Zn2+ alter the metabolism of Se4 is not known. Whether the resulting effect between two trace elements is due to competition for an active site on a biologically active compound, or competition for an active transport carrier across a cell membrane, or masking by complexing remains a matter of pure speculation. It has been shown that certain trace elements have a significant effect on the normal metabolism and excretion of selenium. Evidence suggests that there is a reaction between selenium and zinc and cadmium, while selenium appears to prevent arsenic and tellurium from reaching target tissues.

Incorporation of Selenium-75 into Dog Hair

Summary Trace amounts of Se75 injected subcutaneously into dogs as either Se75O3 were deposited and retained in hair for as long as 316 days. Se75 was found in the cystine-rich protein keratin when the latter was isolated as the thiosulfate, S-sulfo-kerateine, and in the cystine fraction isolated from hair. The source of selenium which is incorporated into hair protein is discussed. The technical assistance of Benjamin R. Larke is gratefully acknowledged.

Methionine-Selenomethionine Parallels in E. coli Polypeptide Chain Initiation and Synthesis

Summary Using a cell-free synthesizing system and natural messenger (f2 viral RNA), we observed that selenomethionyl-tRNA participated in polypeptide synthesis to about the same extent as methionyl-tRNA. Studies on the role of Se Met in the initiation of protein synthesis indicated that N-formyl Se Met-tRNA can function as an initiator of protein synthesis as it has been established for N-formyl Met-tRNA. It is concluded that in E. coli Se Met is incorporated into polypeptides via the Met pathway, including the initiation mechanism involving the N-formylated aminoacyl-tRNA. Acknowledgement is made to Dr. J. C. Rabinowitz for crystalline formyltetrahydrofolate synthetase [J. Biol. Chem. 237, 2898 (1962)].

Radioactivation as a method for preparing 75Se-labelled selenium compounds

Chemically pure 6-selenoquinone, 6-selenopurine, and selenocystine were activated by irradiation in the watercooled compartment of a graphite reactor at a neutron flux of 7.5 x 10/sup 11/ neutrons/cm/sup 2/sec for 62 hr. After irradiation the Se/sup 75/ content of the compounds was determined by use of a gamma scintillation chamber. No evidence was found of decomposition during the activation procedure. (C.H.)

Influence of selenium on the growth of N-nitrosomethylurea-induced mammary tumor cells in culture

Abstract Selenium is an essential dietary trace element which has anticancer properties. Among its effects in rats, selenium has been shown to inhibit the development of carcinogen-induced mammary tumors by interfering with the postinitiation, promotion phase of carcinogenesis. We studied the effects of selenium on the growth of rat mammary tumor cells in primary culture. Our objective was to determine whether selenium had any direct influence on cell growth which might explain its influence on tumor development. Rat mammary tumors were induced by N-nitrosomethylurea. Tumor epithelium was prepared by collagenase dispersion and the cells were separated by Ficoll gradient centrifugation. The tumor epithelium was grown in primary culture using a defined serum-free medium. The addition of low concentrations of sodium selenite, less than 1.0 μg/ml, stimulated tumor cell proliferation. Protein synthesis and the production of type IV collagen increased within the first hour of exposure, prior to any measurable increase in DNA synthesis. Concentrations of selenite greater than 1.0 μg/ml inhibited cell proliferation, the synthesis of protein, and the replication of DNA in a dose-related manner. These studies demonstrated that selenium has the potential to influence the postinitiation phase of rat mammary tumorigenesis by directly altering the growth of tumor cells, possibly through the regulation of protein synthesis.

Parallelism Between Sulfur and Selenium Amino Acids in Protein Synthesis in the Skin of Zinc-Deficient Rats

Summary Feeding animals a diet low in either zinc or selenium causes an abnormal condition of skin and hair. It has been established (7, 8) that the uptake of L-cystine-35S and L-methionine-35S in the skin protein of the ZnD rats was significantly lower than in the zinc-supplemented pair-fed controls (ZnS), i.e., 30 and 60%, respectively. Studies were made to investigate the parallelism between the sulfur (Met and Cyst) and selenium (Se Met and Se Cyst) amino acids in protein synthesis in the skin from ZnD rats. Results indicate that at 24 hr the specific activity (cpm/mg protein) present in the skin of the ZnD rats was 25 and 58% of that of the pair-fed controls, after injection of L-75Se Met and L-75Se Cyst, respectively. No significant differences were observed in the 75Se content of the liver, kidney and muscle between the two groups, which was also true with the sulfur amino acids. These results clearly establish a parallelism between sulfur and selenium amino acids in protein synthesis and strongly suggest that zinc plays a role in the metabolism of Se Met and Se Cyst in protein synthesis in the skin.

Selenium deficiency and protein, RNA and DNA synthesis in rat pancreas and liver.

Summary Rats on a selenium-deficient torula yeast diet containing 100 mg Vitamin E/kg compared to a similar diet with 0.5 ppm selenium as sodium selenite do not show any decrease in protein, RNA and DNA synthesis in the pancreas or liver. The gross depression and change of pancreatic enzymes found in the chick on selenium-deficient diet were not apparent in the rat on a selenium-deficient diet.