Genotoxicity of 15-deoxygoyazensolide in bacteria and yeast.
Sesquiterpene lactones (SLs) present a wide range of pharmacological activities. The aim of our study was to investigate the genotoxicity of 15-deoxygoyazensolide using the Salmonella/microsome assay and the yeast Saccharomyces cerevisiae. We also investigated the nature of induced DNA damage using yeast strains defective in DNA repair pathways, such as nucleotide excision repair (RAD3), error prone repair (RAD6), and recombinational repair (RAD52), and in DNA metabolism, such as topoisomerase mutants. 15-deoxygoyasenzolide was not mutagenic in Salmonella typhimurium, but it was mutagenic in S. cerevisiae. The hypersensitivity of the rad52 mutant suggests that recombinational repair is critical for processing lesions resulting from 15-deoxygoyazensolide-induced DNA damage, whereas excision repair and mutagenic systems does not appear to be primarily involved. Top 1 defective yeast strain was highly sensitive to the cytotoxic activity of 15-deoxygoyazensolide, suggesting a possible involvement of this enzyme in the reversion of the putative complex formation between DNA and this SL, possibly due to intercalation. Moreover, the treatment with this lactone caused dose-dependent glutathione depletion, generating pro-oxidant status which facilitates oxidative DNA damage, particularly DNA breaks repaired by the recombinational system ruled by RAD52 in yeast. Consistent with this finding, the absence of Top1 directly affects chromatin remodeling, allowing repair factors to access oxidative damage, which explains the high sensitivity to top1 strain. In summary, the present study shows that 15-deoxygoyazensolide is mutagenic in yeast due to the possible intercalation effect, in addition to the pro-oxidant status that exacerbates oxidative DNA damage.
Vasconcellos
Marne C
MC
Departamento de Fisiologia e Farmacologia, Faculdade de Medicina, Universidade Federal do Ceará, Caixa Postal-3157, 60430-270 Fortaleza, Ceará, Brazil.
Rosa
Renato M
RM
Machado
Miriana S
MS
Villela
Izabel V
IV
Crotti
Antônio Eduardo Miller
AE
Lopes
João Luis Callegari
JL
Pessoa
Cláudia
C
de Moraes
Manoel Odorico
MO
Lopes
Norberto Peporine
NP
Costa-Lotufo
Letícia V
LV
Saffi
Jenifer
J
Henriques
João Antônio Pegas
JA
D001483:Base Sequence; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics; D004269:DNA, Bacterial / Q000235:genetics; D005978:Glutathione / Q000378:metabolism; D006575:Heterocyclic Compounds, 3-Ring / Q000633:toxicity*; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity*; D009154:Mutation; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D012486:Salmonella typhimurium / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism
C498361:15-deoxygoyazensolide; D004269:DNA, Bacterial; D006575:Heterocyclic Compounds, 3-Ring; D009153:Mutagens; D005978:Glutathione