Characteristics of selenazolidine prodrugs of selenocysteine: toxicity, selenium levels, and glutathione peroxidase induction in A/J mice

We have previously reported the synthesis and characterization of two new classes of selenazolidine-4(R)-carboxylic acids (2-oxo and 2-methyl-SCAs) (OSCA and MSCA, respectively), as well as the "parent" compound, selenazolidine-4(R)-carboxylic acid (SCA, selenaproline). These compounds were designed as prodrugs of L-selenocysteine with potential application in cancer chemoprevention or other clinical uses. We will be exploring the chemopreventive activity of the new compounds in the well-established A/J mouse model of tobacco-induced lung carcinogenesis. The objectives of the present study were to investigate several fundamental biochemical endpoints after selenazolidine administration compared with other selenium-containing agents. Groups of mice were fed either AIN-76A diet alone or the diet supplemented with the following selenium compounds (ppm Se): sodium selenite (5), L-selenomethionine (3.75), L-selenocystine (15), Se-methyl-L-selenocysteine (3), MSCA (5, 10, or 15), OSCA (5, 10, or 15), or SCA (5, 10, or 15). After 28 days of supplementation, toxicity of the selenazolidines was not evident, as measured by outward appearance and behavior, body and organ weight changes, and histological evaluation of liver and lung tissue. Select treatment groups showed significant increases in selenium levels in blood and tissues. Increased activity of selenium-dependent glutathione peroxidase (GPx) in blood and liver illustrated that the selenazolidines provided a source of biologically-available selenium.     

Chemopreventive activity of selenocysteine prodrugs against tobacco‐derived nitrosamine (NNK) induced lung tumors in the A/J mouse

Prodrugs of L ‐selenocysteine have potential utility in cancer chemoprevention. This study reports the efficacy of three selenazolidine‐4(R)‐carboxylic acids, (2‐unsubstituted, 2‐oxo, and 2‐methyl derivatives; SCA, OSCA, and MSCA, respectively) against tobacco‐related lung tumorigenesis in a mouse model. Seven days after initiation of an AIN‐76A diet supplemented with sodium selenite (5 ppm Se), L ‐selenomethionine (3.75 ppm Se), Se‐methyl‐L ‐selenocysteine (3 ppm Se), L ‐selenocystine (15 ppm Se), SCA (15 ppm Se), OSCA (15 ppm Se), or MSCA (15 ppm Se), mice received 4‐(methylnitrosamino)‐1‐(3‐pyridyl)‐1‐butanone (NNK; 10 μmol, i.p.). After an additional 16 weeks on the diets, two compounds, OSCA and selenocystine, significantly reduced lung adenoma multiplicity from 7.2 tumors per mouse in the NNK group to 4.5 and 4.6 tumors per mouse, respectively. Neither selenium concentration nor glutathione peroxidase activity in either RBCs or liver served as surrogate indicators of tumor reduction. Hepatic selenium levels were significantly elevated by all selenium‐containing compounds except Se‐methyl‐L ‐selenocysteine and SCA; RBC selenium levels by all except sodium selenite and MSCA. With the exception of L ‐selenomethionine, RBC glutathione peroxidase activity was increased along with the elevated selenium levels. Hepatic glutathione peroxidase activity was elevated by all Se‐compounds except SCA. The two compounds showing significant tumor reduction (OSCA and selenocystine) were the only two compounds that showed ubiquity of changes, elevating both selenium levels and GPx activity in both liver and RBC. © 2005 Wiley Periodicals, Inc. J Biochem Mol Toxicol 19:396‐405, 2005; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/jbt.20105