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.
Li
Liang
L
Department of Medicinal Chemistry, University of Utah, Salt Lake City, UT 84112, USA.
Xie
Yang
Y
El-Sayed
Wael M
WM
Szakacs
Juliana G
JG
Roberts
Jeanette C
JC
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004790:Enzyme Induction; D005260:Female; D005979:Glutathione Peroxidase / Q000096:biosynthesis* / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D009929:Organ Size / Q000187:drug effects; D016566:Organoselenium Compounds / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity*; D011355:Prodrugs / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity*; D011392:Proline / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity*; D012643:Selenium / Q000097:blood / Q000493:pharmacokinetics*; D017279:Selenocysteine / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity*; D014018:Tissue Distribution; D018675:Toxicity Tests
D016566:Organoselenium Compounds; D011355:Prodrugs; D017279:Selenocysteine; C014811:selenaproline; D011392:Proline; D005979:Glutathione Peroxidase; D012643:Selenium