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 incre ases in known selenoenzymes. There has been no information on whether selen oenzymes are obligatory mediators of the anticarcinogenic effect of seleniu m. Our previous experience with triphenyl-selenonium chloride suggests that it might be an ideal agent for studying selenium chemoprevention while sim ultaneously precluding the synthesis of selenoenzymes. Triphenylselenonium chloride has excellent tumor inhibitory activity but does not support the r epletion of selenoenzymes in animals that have been deprived of a bioavaila ble form of selenium. In the present experiments, we evaluated the efficacy of mammary cancer protection by this compound in rats fed either a selenit e-deficient (<0.01 ppm Se) or selenite-adequate (0.1 ppm Se) diet. We also measured the activities of liver glutathione peroxidase and thioredoxin red uctase as markers of selenium bioavailability in these differ ent treatment conditions. In carcinogen-treated control animals not receiving triphenyls elenonium 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 nutritio nal status. However; this supplement had little effect on tissue selenium l evels and did not increase liver glutathione peroxidase or thioredoxin redu ctase activities. In contrast, a level of 0.1 ppm Se as selenite did not af fect mammary tumorigenesis but markedly increased tissue selenium concentra tions and selenoenzyme activities. It is concluded that triphenylselenonium chloride does not release inorganic selenium for selenoprotein synthesis a nd that its anticancer activity involves mechanisms that are probably intri nsic to the compound This study also shows for the first time that selenium chemoprevention is possible in an environment of severely depressed seleno enzyme expression. Thus selenium chemoprevention efficacy can be separated experimentally from selenoprotein synthesis using this model system.