Piplartine induces genotoxicity in eukaryotic but not in prokaryotic model systems.

Piplartine {5,6-dihydro-1-[(2E)-1-oxo-3-(3,4,5-trimethoxyphenyl)-2-propen-1-yl]-2(1H)-pyridinone} is an alkamide present in Piper species that exhibits promising anticancer properties. It was previously shown that piplartine is mutagenic in yeast and cultured mammalian cells. This study was performed to increase the knowledge on the mutagenic potential of piplartine using the Salmonella/microsome assay, V79 cell micronucleus and chromosome aberration assays, and mouse bone-marrow micronucleus tests. Piplartine was isolated from the roots of Piper tuberculatum. This extracted compound was unable to induce a mutagenic response in any Salmonella typhimurium strain either in the presence or absence of metabolic activation. Piplartine showed mutagenic effects in V79 cells, as there was an increased frequency of aberrant cells and micronuclei formation. In addition, piplartine administered at 50mg/kg did not induce micronucleus formation in vivo, but a dose of 100mg/kg induced an increase in the levels of micronucleus polychromatic erythrocytes (MNPCEs). Overall, these results provide further support that piplartine induces in vivo and in vitro mutagenicity in eukaryotic models.

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.