Chemoprevention with triphenylselenonium chloride in selenium-deficient rats.
Cancer chemoprevention by high levels of selenium, including compounds like sodium selenite or selenomethionine, is generally not accompanied by increases in known selenoenzymes. There has been no information on whether selenoenzymes are obligatory mediators of the anticarcinogenic effect of selenium. Our previous experience with triphenylselenonium chloride suggests that it might be an ideal agent for studying selenium chemoprevention while simultaneously precluding the synthesis of selenoenzymes. Triphenylselenonium chloride has excellent tumor inhibitory activity but does not support the repletion of selenoenzymes in animals that have been deprived of a bioavailable form of selenium. In the present experiments, we evaluated the efficacy of mammary cancer protection by this compound in rats fed either a selenite-deficient (< 0.01 ppm Se) or selenite-adequate (0.1 ppm Se) diet. We also measured the activities of liver glutathione peroxidase and thioredoxin reductase as markers of selenium bioavailability in these different treatment conditions. In carcinogen-treated control animals not receiving triphenylselenonium chloride, mammary tumor incidence and the total number of tumors were similar between the selenite-deficient and selenite-adequate groups. Thus the correction of selenium deficiency by the addition of 0.1 ppm Se as selenite did not have detectable anticarcinogenic effects. Supplementation of triphenylselenonium chloride at a level of 30 ppm Se suppressed mammary tumorigenesis by approximately 50% regardless of dietary selenium nutritional status. However, this supplement had little effect on tissue selenium levels and did not increase liver glutathione peroxidase or thioredoxin reductase activities. In contrast, a level of 0.1 ppm Se as selenite did not affect mammary tumorigenesis but markedly increased tissue selenium concentrations and selenoenzyme activities. It is concluded that triphenylselenonium chloride does not release inorganic selenium for selenoprotein synthesis and that its anticancer activity involves mechanisms that are probably intrinsic to the compound. This study also shows for the first time that selenium chemoprevention is possible in an environment of severely depressed selenoenzyme expression. Thus selenium chemoprevention efficacy can be separated experimentally from selenoprotein synthesis using this model system.
Ip
C
C
Department of Experimental Pathology, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263, USA. Clement.Ip@RoswellPark.org
Lisk
D J
DJ
Ganther
H E
HE
D000818:Animals; D002273:Carcinogens; D003454:Cryptococcus; D005260:Female; D005979:Glutathione Peroxidase / Q000378:metabolism; D008099:Liver / Q000201:enzymology; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000517:prevention & control*; D008770:Methylnitrosourea; D016566:Organoselenium Compounds / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012643:Selenium / Q000172:deficiency* / Q000378:metabolism; D018038:Sodium Selenite / Q000008:administration & dosage; D013047:Specific Pathogen-Free Organisms; D013880:Thioredoxin-Disulfide Reductase / Q000378:metabolism
D002273:Carcinogens; D016566:Organoselenium Compounds; C092819:triphenylselenonium chloride; D008770:Methylnitrosourea; D005979:Glutathione Peroxidase; D013880:Thioredoxin-Disulfide Reductase; D012643:Selenium; D018038:Sodium Selenite