DNA damage in tissues and organs of mice treated with diphenyl diselenide.
Diphenyl diselenide (DPDS) is an organoselenium compound with interesting pharmacological activities and various toxic effects. In previous reports, we demonstrated the pro-oxidant action and the mutagenic properties of this molecule in bacteria, yeast and cultured mammalian cells. This study investigated the genotoxic effects of DPDS in multiple organs (brain, kidney, liver, spleen, testes and urinary bladder) and tissues (bone marrow, lymphocytes) of mice using in vivo comet assay, in order to determine the threshold of dose at which it has beneficial or toxic effects. We assessed the mechanism underlying the genotoxicity through the measurement of GSH content and thiobarbituric acid reactive species, two oxidative stress biomarkers. Male CF-1 mice were given 0.2-200 micromol/kg BW DPDS intraperitonially. DPDS induced DNA damage in brain, liver, kidney and testes in a dose response manner, in a broad dose range at 75-200 micromol/kg with the brain showing the highest level of damage. Overall, our analysis demonstrated a high correlation among decreased levels of GSH content and an increase in lipid peroxidation and DNA damage. This finding establishes an interrelationship between pro-oxidant and genotoxic effects. In addition, DPDS was not genotoxic and did not increase lipid peroxidation levels in any organs at doses < 50 micromol/kg. Finally, pre-treatment with N-acetyl-cysteine completely prevented DPDS-induced oxidative damage by the maintenance of cellular GSH levels, reinforcing the positive relationship of DPDS-induced GSH depletion and DNA damage. In summary, DPDS induces systemic genotoxicity in mammals as it causes DNA damage in vital organs like brain, liver, kidney and testes.
Rosa
Renato Moreira
RM
Departamento de Biofísica, Instituto de Biociências, Universidade Federal do Rio Grande do Sul (UFRGS), Avenida Bento Gonçalves 9500, Bairro Agronomia, CEP 91501-970 Porto Alegre, RS, Brazil.
Hoch
Nícolas Carlos
NC
Furtado
Gabriel Vasata
GV
Saffi
Jenifer
J
Henriques
João Antonio Pêgas
JA
D000111:Acetylcysteine / Q000627:therapeutic use; D000818:Animals; D001555:Benzene Derivatives / Q000633:toxicity*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects; D020552:Comet Assay; D004249:DNA Damage / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D016166:Free Radical Scavengers / Q000627:therapeutic use; D005978:Glutathione / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008214:Lymphocytes / Q000187:drug effects*; D008297:Male; D051379:Mice; D009152:Mutagenicity Tests; D009924:Organ Culture Techniques; D016566:Organoselenium Compounds / Q000633:toxicity*; D016877:Oxidants / Q000633:toxicity*; D014018:Tissue Distribution
D001555:Benzene Derivatives; D016166:Free Radical Scavengers; D016566:Organoselenium Compounds; D016877:Oxidants; C061132:diphenyldiselenide; D005978:Glutathione; D000111:Acetylcysteine