title: Dicholesteroyl diselenide: cytotoxicity, genotoxicity and mutagenicity in the yeast Saccharomyces cerevisiae and in Chinese hamster lung fibroblasts.
abstract: The organoselenium compound, dicholesteroyl diselenide (DCDS) is a structural analogue of diphenyl diselenide (DPDS) and may be considered as a promising antioxidant drug in vivo. Nevertheless, little is known about the toxicological properties of DCDS. In the present study we evaluated the cytotoxic, genotoxic and mutagenic properties of DCDS in Chinese hamster lung fibroblasts (V79) and in strains of the yeast Saccharomyces cerevisiae, proficient and deficient in several DNA-repair pathways. The results with V79 cells show that DCDS induced cytotoxicity, GSH depletion and elevation of lipid peroxidation at lower concentrations than did DPDS. DCDS also generated single- and double-strand DNA breaks in V79 cells, both in the presence and in the absence of metabolic activation, as revealed by alkaline and neutral comet assays. Moreover, the induction of oxidative DNA base-damage was demonstrated by means of a modified comet assay with formamidopyrimidine-DNA glycosylase and endonuclease III. Treatment with DCDS also induced micronucleus formation in V79 cells as well as point and frame-shift mutations in a haploid wild-type strain of S. cerevisiae. Yeast mutants defective in base excision-repair proteins were the most sensitive to DCDS. Pre-incubation with N-acetylcysteine reduced DCDS's oxidative, genotoxic and mutagenic effects in yeast and in V79 cells. Our findings indicate that the presence of cholesteroyl substituents in DCDS results in elevation of its cytotoxic and genotoxic potential compared with that of DPDS in yeast and in V79 cells. However, due to dose-dependent contrasting behaviour of organoselenium compounds and differences in their toxicity in in vitro and in vivo systems, further studies are needed in order to establish the non-toxic concentration range for treatment in mammals.
authors.affiliation: Departamento de Biofísica, Instituto de Biociências, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil.
authors.forename: Iuri Marques
authors.initials: IM
authors.lastname: de Oliveira
authors.affiliation: Departamento de Biofísica, Instituto de Biociências, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil.
authors.forename: Tiago Hoerbe
authors.initials: TH
authors.lastname: Degrandi
authors.affiliation: Departamento de Biofísica, Instituto de Biociências, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil.
authors.forename: Patrícia Mendes
authors.initials: PM
authors.lastname: Jorge
authors.affiliation: Departamento de Ciências Básicas da Saúde, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre, RS, Brazil.
authors.forename: Jenifer
authors.initials: J
authors.lastname: Saffi
authors.affiliation: Laboratório de Genética Toxicológica, Universidade Luterana do Brasil (ULBRA), Canoas, RS, Brazil.
authors.forename: Renato Moreira
authors.initials: RM
authors.lastname: Rosa
authors.affiliation: Departamento de Biofísica, Instituto de Biociências, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil. Electronic address: tgesheva@gmail.com.
authors.forename: Temenouga Nikolova
authors.initials: TN
authors.lastname: Guecheva
authors.affiliation: Departamento de Biofísica, Instituto de Biociências, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil; Instituto de Biotecnologia, Departamento de Ciências Biomédicas, Universidade de Caxias do Sul - UCS, Caxias do Sul, RS, Brazil.
authors.forename: João Antonio Pêgas
authors.initials: JA
authors.lastname: Henriques
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000032:analysis; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002784:Cholesterol / Q000031:analogs & derivatives* / Q000633:toxicity; D020552:Comet Assay; D006224:Cricetinae; D003412:Cricetulus; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D016368:Frameshift Mutation / Q000187:drug effects; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D048629:Micronuclei, Chromosome-Defective / Q000139:chemically induced*; D015162:Micronucleus Tests; D009153:Mutagens / Q000633:toxicity*; D016566:Organoselenium Compounds / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000235:genetics; D018675:Toxicity Tests / Q000379:methods
chemical_list: D015415:Biomarkers; D009153:Mutagens; D016566:Organoselenium Compounds; C539240:dicholesteroyl diselenide; D002784:Cholesterol
keywords: Dicholesteroyl diselenide; Diphenyl diselenide; Genotoxicity; Oxidative stress; Saccharomyces cerevisiae; V79 cells