ABSTRACT
BACKGROUND AND OBJECTIVES: 3,3' Diseleno dipropionic acid (DSePA), a synthetic compound has been shown to have radioprotective activity, especially as a lung radioprotector. In this study, the pharmacokinetics and biodistribution of DSePA in MX-1 tumour bearing SCID mice were evaluated. METHODS: Twenty SCID mice were administered DSePA (50 mg/kg bodyweight) by oral gavage following which four animals each were sacrificed at 15, 30 min, 1, 2 and 4 h. Blood and tissue samples were collected for determination of DSePA concentration by graphite furnace atomic absorption spectrometry (GFAAS) method. The control group (n = 4) was administered sterile water and sacrificed at 4 h. RESULTS: Peak plasma concentration (C max) of 2.7 µg/ml was observed at 15 min which returned to near baseline (baseline = 0.6 µg/ml) at 1 h following drug administration. Biphasic pharmacokinetics characterized by rapid distribution phase and a slower elimination phase were observed. Highest maximal concentration (C max) of the drug was observed in lung (19.2 µg/g at 30 min) followed by intestine (14.64 µg/g at 15 min) and kidney (12.96 µg/g at 15 min). There was negligible uptake in tumor tissue and no uptake in brain. CONCLUSIONS: DSePA has a favorable pharmacokinetic profile which makes it a potentially good candidate for further development as a radioprotective agent.
Subject(s)
Drugs, Chinese Herbal/pharmacokinetics , Free Radical Scavengers/pharmacokinetics , Lung/metabolism , Propionates/pharmacokinetics , Radiation-Protective Agents/pharmacokinetics , Selenium Compounds/pharmacokinetics , Administration, Oral , Animals , Area Under Curve , Blood-Brain Barrier/metabolism , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cell Line, Tumor , Drugs, Chinese Herbal/administration & dosage , Drugs, Chinese Herbal/metabolism , Female , Free Radical Scavengers/administration & dosage , Free Radical Scavengers/blood , Free Radical Scavengers/metabolism , Half-Life , Humans , Lung/pathology , Metabolic Clearance Rate , Mice, SCID , Organ Specificity , Propionates/administration & dosage , Propionates/blood , Propionates/metabolism , Radiation-Protective Agents/administration & dosage , Radiation-Protective Agents/metabolism , Selenium Compounds/administration & dosage , Selenium Compounds/blood , Selenium Compounds/metabolism , Spectrophotometry, Atomic , Tissue Distribution , Tumor Burden , Xenograft Model Antitumor AssaysABSTRACT
Our previous study showed that 3,3'-diselenodipropionic acid (DSePA), a simple, stable, and water-soluble organoselenium exhibiting glutathione peroxidase (GPx)-like activity offered good radioprotection under in vitro and in vivo conditions. Herein, we investigated the anti-genotoxic effect of DSePA in model cellular systems such as Chinese Hamster Ovary (CHO) cell line and human peripheral lymphocytes after exposure to γ-radiation. The measurements on the induction of γ-H2AX foci and micronuclei frequency in the cell nuclei indicated that pretreatment with DSePA significantly prevented the radiation induced DNA damage or genotoxicity and subsequent cytotoxicity without exerting its own toxicity. The maximum protective effect of DSePA was seen at a pre-treatment concentration of 3 µg/ml. The mechanistic investigations in CHO cells revealed that DSePA pretreatment prevented the radiation induced ROS generation, lipid peroxidation and subsequent apoptosis in these cells. Further, it was seen to augment the mRNA expressions of GPx2 significantly and GPx4 marginally without causing much change in the total GPx activity after radiation exposure. These results suggested the roles of GPx2 and GPx4 in DSePA mediated radioprotection. In conclusion our results confirm the nongenotoxic nature of the DSePA and validate its radioprotective efficacy and mechanisms of action in model cellular systems.