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

Life Sciences Group, IIT Research Institute, Chicago, IL 60616, USA.
Food and Chemical Toxicology (Impact Factor: 2.9). 03/2008; 46(3):1068-78. DOI: 10.1016/j.fct.2007.11.001
Source: PubMed


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.

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    • "Se was first discovered in 1817 in the form of a reddish precipitate, an elemental form of Se (Zhang, 2009). Elemental Se was originally considered to biologically inert in upregulating selenoenzymes and consequently most work has focused on organic forms such as selenomethionine and Se-methylselenocysteine, and on inorganic sodium selenate and selenite (Weekley and Harris, 2013; Schrauzer, 2000; Johnson et al., 2008). Materials at nanometer dimensions or with nanostructures almost invariably exhibit new properties different from those of either bulk materials or isolated atoms. "
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    ABSTRACT: Elemental selenium nanoparticles (SeNPs) have been demonstrated to be equivalent to selenomethionine and methylselenocysteine in upregulating selenoenzymes; however, the toxicity of SeNPs is markedly lower than these two organic selenium compounds. The objective of this study was to determine the effect of SeNP size on cancer cell growth and ascertain whether production of reactive oxygen species (ROS) is implicated as a candidate mechanism of action. Two types of SeNPs (averaging 35 nm and 91 nm) were investigated. Cell accumulation was inhibited in vitro and in vivo in a manner inversely proportional to particle size. In vitro modeling experiments showed the reduction of SeNPs to be glutathione concentration dependent and to result in ROS formation. Both SeNP biotransformation and ROS production were size dependent, with the smaller SeNPs being more active, thereby suggesting that small-sized SeNPs are more effective in inhibiting cancer cell proliferation through an ROS mediated mechanism. Copyright © 2015. Published by Elsevier Ltd.
    Food and chemical toxicology: an international journal published for the British Industrial Biological Research Association 08/2015; DOI:10.1016/j.fct.2015.08.006 · 2.90 Impact Factor
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    • "SeMSC is considered to be one of the most effective Se compounds for chemoprevention, but unfortunately its systemic toxicities are high as well.112–114 Zhang et al111 have demonstrated that SeMSC and Nano-Se have equal bioavailability at nutritional doses. "
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    ABSTRACT: Chemoprevention that impedes one or more steps in carcinogenesis, via long-term administration of naturally occurring or synthetic compounds, is widely considered to be a crucial strategy for cancer control. Selenium (Se) has chemopreventive effects, but its application is limited due to a low therapeutic index as shown in numerous animal experiments. In contrast to Se, which was known for its toxicity prior to the discovery of its beneficial effects, the natural compound epigallocatechin-3-gallate (EGCG) was originally considered to be nontoxic. Due to its preventive effects on many types of cancer in various animal models, EGCG has been regarded as a prime example of a promising chemopreventive agent without major toxicity concerns. However, very recently, evidence has accumulated showing that efficacious doses of EGCG used in health promotion may not be far from its toxic dose level. Therefore, both Se and EGCG need to be modified by novel pharmaceutical technologies to attain enhanced efficacy and/or reduced toxicity. Nanotechnology may be one of these technologies. In support of this hypothesis, the characteristics of polylactic acid and polyethylene glycol-encapsulated nano-EGCG and elemental Se nanoparticles dispersed by bovine serum albumin are reviewed in this article. Encapsulation of EGCG to form nano-EGCG leads to its enhanced stability in plasma and remarkably superior chemopreventive effects, with more than tenfold dose advantages in inducing apoptosis and inhibition of both angiogenesis and tumor growth. Se at nanoparticle size ("Nano-Se"), compared with Se compounds commonly used in dietary supplements, has significantly lower toxicity, without compromising its ability to upregulate selenoenzymes at nutritional levels and induce phase II enzymes at supranutritional levels.
    International Journal of Nanomedicine 03/2012; 7:1711-21. DOI:10.2147/IJN.S29341 · 4.38 Impact Factor
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    • "The toxicity of this species of Se is probably at least as high as other forms; toxicity to rats occurred at doses >0.5 mg/kg BW (Johnson et al., 2008). Typically, the maximum tolerable level of Se for sheep and cattle is given as 5 mg/kg diet dry matter (NRC, 2005). "
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    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; 90(1-3). DOI:10.1016/j.smallrumres.2010.02.009 · 1.13 Impact Factor
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