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

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 < 0.5 mg/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.

Safety evaluation of Se-methylselenocysteine as nutritional selenium supplement: Acute toxicity, genotoxicity and subchronic toxicity

“…A subacute toxicity study found that SeMC induced dose-related hepatomegaly and hepatocellular degeneration in rats and dogs after 28-day treatment (Johnson et al, 2008). In agreement, our 90-day subchronic toxicity study demonstrated that the relative liver weight was dose-dependently increased by SeMC in both male and female rats.…”

Influence of Alternative Tubulin Inhibitors on the Potency of Epirubicin-Immunochemotherapeutic Synthesized with an Ultra Violet Light-Activated Intermediate

“…Various organoselenium compounds including methylselenocysteine are known to exert cytotoxic anti-neoplastic properties against mammary adenocarcinoma/carcinoma (Coyne et al, 2011; Ip & Dong 2001; Johnson, Morrissey, Kapetanovic, Crowell, & McCormick 2008; Li et al, 2009; Medina, Thompson, Ganther, & Ip 2001) and other cancer cell types (Cao, Durrani, & Rustum 2004; Chintala et al, 2010) while also enhancing the potency of anthracyclines (Coyne et al, 2011; Juliger, Goenaga-Infante, Lister, Fitzgibbon, & Joel 2007; Li, Zhou, Dong & Ip C 2007; Li, Zhou, Wang, Zhang, Dong, & Ip 2007) and covalent epirubicin-immunochemotherapeutics (Coyne et al, 2011). Somewhat surprisingly the cytotoxic anti-neoplastic potency of griseofulvin against mammary adenocarcinoma (SKBr-3) was substantially greater than molar-equivalent (standardized) concentrations of methylselenocysteine (Figure 6).…”

Inverse relationship between elemental selenium nanoparticle size and inhibition of cancer cell growth in vitro and in vivo

“…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).…”