Metabolites of sodium selenite and methylated selenium compounds administered at cancer chemoprevention levels in the rat

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Abstract
1. The metabolism of orally-administered sodium selenite and five methylated selenium compounds was investigated in the female rat at dosages equivalent to those used in other studies for prevention of mammary cancer. Dimethyl selenide (DMSe) exhaled within 24 h following dosing was measured, along with inorganic and monomethylated (MMSe) forms of selenium plus trimethylselenonium ion (TMSe+) in urine. 2. MMSe was the dominant metabolite of selenite given at low levels (0-1 ppm in the diet), but excretion of DMSe and TMSe+ increased sharply when selenite dosage was increased to the chemopreventive range of 3 ppm dietary Se. When similar chemopreventive levels of mono-, di-, or trimethylated compounds were administered, the total quantity of methylated metabolites was greater than for selenite and the metabolite profile reflected the expected point of entry into the intermediary metabolism pathway; the major metabolites were MMSe from Se-methylselenocysteine, DMSe from selenobetaine methyl ester, and TMSe+ from selenobetaine. However, the profile of metabolites provided clear evidence that the methylated selenium compounds underwent demethylation, as shown by the excretion of inorganic and MMSe. Selenium administered as dimethyl selenoxide was almost completely excreted and about 90% of the dose was recovered as DMSe, indicating that reduction was the major pathway. For TMSe+, about 10% of the dose was excreted as DMSe and 84% as TMSe+. 3. A low, non-toxic level of sodium arsenite (5 ppm As in the diet) that is known to modify differentially the anticarcinogenic activity of selenite and methylated selenium compounds did not modify the excretion of the methylated selenium metabolites. 4. It is concluded that high anticarcinogenic activity is associated with extensive excretion of methylated Se excretory metabolites, but high output of such metabolites per se does not necessarily lead to anticarcinogenic activity. The whole animal has extensive capabilities for interconverting forms of selenium, and retains significant amounts in tissues, complicating the interpretation of Se metabolism and anticarcinogenic action. Further research is needed on the forms of selenium present in tissues.