Subchronic oral toxicity studies of Se-methylselenocysteine, an organoselenium compound for breast cancer prevention

Life Sciences Group, IIT Research Institute, Chicago, IL 60616, USA.
Food and Chemical Toxicology (Impact Factor: 2.61). 03/2008; 46(3):1068-78. DOI: 10.1016/j.fct.2007.11.001
Source: PubMed

ABSTRACT Se-methylselenocysteine (MSC) is an organoselenium compound being developed for breast cancer chemoprevention. To characterize MSC toxicity, CD rats received daily gavage doses of 0, 0.5, 1.0, or 2.0 mg/kg/day (0, 3, 6, or 12 mg/m(2)/day), and beagle dogs received daily gavage doses of 0, 0.15, 0.3, or 0.6 mg/kg/day (0, 3, 6, or 12 mg/m(2)/day) for 28 days. In rats, MSC induced dose-related hepatomegaly in both sexes; mild anemia, thrombocytopenia, and elevated liver enzymes were observed in high dose females only. Microscopic pathology included hepatocellular degeneration (high dose males, all doses in females); arrested spermatogenesis (high dose males); and atrophy of corpora lutea (middle and high dose females). In dogs, MSC induced mild anemia in middle and high dose males, and in high dose females. Toxicologically significant microscopic lesions in dogs were seen only in the liver (peliosis and vacuolar degeneration in high dose males, midzonal necrosis in males in all dose groups). Based on liver pathology seen in female rats in all dose groups, the no observed adverse effect level (NOAEL) for MSC in rats is <0.5mg/kg/day. Based on alterations in hematology parameters and liver morphology in male dogs in all dose groups, the NOAEL for MSC in dogs is <0.15 mg/kg/day.

Download full-text


Available from: David L Mccormick, Jun 28, 2015
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Grazing livestock frequently ingest toxic plants, occasionally with fatal results. Behavioral adjustments by livestock may reduce toxin intake; for example they can develop food aversions which may protect animals from over-ingestion of toxic plants. The purpose of this study was to evaluate three plants with different mechanisms of toxicity for their efficacy in conditioning a taste aversion: (1) a seleniferous plant, Xylorhiza glabriuscula, (2) an indolizidine alkaloid-containing plant, Astragalus lentiginosus, and (3) a diterpene acid-containing plant, Gutierrezia sarothrae. For each plant species, 15 sheep were divided into 3 treatment groups and periodically tested for consumption of a novel food, whole corn: (1) controls - given 200g of ground alfalfa hay by oral gavage, (2) averted - given lithium chloride (LiCl) at 175mg/kg BW via oral gavage, and (3) given the specific target plant by oral gavage. X. glabriuscula was given at a dose equivalent to 3mg Se/kg BW; A. lentiginosus was given at a dose equivalent to 3mg/kg of the toxic alkaloid, swainsonine; freshly thawed G. sarothrae was dosed at 5g/kg body weight (BW). Both LiCl and Xylorhiza conditioned an aversion to corn, with sheep eating 1.6 and 0.6% of offered corn during the final test; controls were not averted, eating 93% of the corn (P <0.01). Sheep were partially averted by Xylorhiza after a single dose, and the aversion was complete after the second dose. Sheep were not averted by A. lentiginosus or G. sarothrae. Of the three toxic plants used in this study, only Xylorhiza conditioned a taste aversion. These results likely reflect differing mechanisms of action of the plant toxin(s) on brain and gut structures important for forming conditioned taste aversions. These results suggest that conditioned aversions to Se-containing plants may help to deter consumption of such plants by grazing ruminants on rangelands.
    Small Ruminant Research 05/2010; DOI:10.1016/j.smallrumres.2010.02.009 · 1.10 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Antidiabetic action of inorganic selenium compounds is commonly accepted. Since in diet selenium mainly exists as selenoamino acids, potential hypoglycemic properties of methylselenocysteine (MSC) were investigated in four groups of rabbits: untreated and MSC-treated control animals as well as alloxan-diabetic and MSC-treated diabetic rabbits. MSC (at a dose of 1mg/kg body weight) was administered daily for 3 weeks via intraperitoneal injection. The data show, that in MSC-treated control animals plasma glucose concentration was diminished, while plasma urea and creatinine levels as well as urine albumin content were elevated and necrotic changes occurred in kidney-cortex. Decreased GSH/GSSG ratios in blood, liver and kidney-cortex were accompanied by increased glutathione peroxidase and glutathione reductase activities and a diminished renal gamma-glutamylcysteine synthetase activity. Death of 50% of control animals was preceded by a dramatic decline in blood glucose concentration. Surprisingly, in MSC-treated diabetic rabbits, plasma glucose levels were either normalized or significantly decreased. Blood and liver GSH/GSSG ratios were increased and renal functions were markedly improved, as indicated by a diminished albuminuria and attenuated histological changes characteristic of diabetes. However, after administration of MSC to diabetic rabbits plasma urea and creatinine levels as well as renal GSH/GSSG ratios were not altered. In view of MSC-induced marked accumulation of selenium in kidneys and liver of control rabbits, accompanied by a decline in blood glucose level, disturbance of glutathione homeostasis and kidney-injury, application of MSC in chemotherapy needs a careful evaluation. On the contrary, MSC supplementation might be beneficial for diabetes therapy due to an improvement of both glycemia and renal function.
    Chemico-biological interactions 12/2008; 177(2):161-71. DOI:10.1016/j.cbi.2008.10.022 · 2.98 Impact Factor
  • Source
    Cancer Epidemiology Biomarkers & Prevention 03/2009; 18(3):698-700. DOI:10.1158/1055-9965.EPI-08-1007 · 4.32 Impact Factor