Efeito modulador do (+)-ácido úsnico sobre os danos genotóxicos, mutagênicos e carcinogênicos induzidos por diferentes agentes químicos in vivo e in vitro

Abstract

Unic acid (UA) is one of the most common and abundant lichen metabolites. The aim of this study was to investigate the effects of usnic acid (UA) on: 1] pre-neoplastic colorectal lesions induced by 1,2-dimethylhydrazine (DMH) using the aberrant crypt foci (ACF) as biomarker in rats; 2] the cytotoxic, genotoxic and modulatory activity of AU on doxorubicin (DXR)-induced genotoxicity in Chinese hamster ovary (CHO) cells, using the cytokinesis-block micronucleus (CBMN) assay; 3] the mutagenic, recombinogenic and carcinogenic activity of UA in Drosophila melanogaster using, respectivey, the Somatic Mutation and Recombination Test (SMART) and the test for detecting epithelial tumor clones (wts test). In FCA assay, male Wistar rats were treated with DMH (40 mg/kg b.w) twice a week for two weeks. UA was administered in dosages of 3.125; 12.5 and 50 mg/kg b.w. Ultrapure water (negative control), Tween 5% (solvent control), solvent control + DMH, and positive control (DMH 160 mg/kg b.w) groups were also included. The animals that received the different doses of UA in association with DMH demonstrated statistically significant reductions in the ACF and aberrant crypts (AC) values when compared to the group treated with DMH alone. In the CBMN assay, UA (7.5; 15 or 30 μg/mL) alone was examined for genotoxicity, and combined with DXR (0.5 μg/mL) for antigenotoxicity. Negative, solvent (DMSO, 0.3 μM) and positive (DXR 0.5 μg/mL) controls were also included. Cells treated with UA (30 μg/mL) induced significant increase in micronuclei frequency when compared to the negative control. For SMART, Larvae of 72±4 h from Drosophila were fed with UA (5.0, 10.0 or 20.0 mM); urethane (10.0 mM) (positive control); and solvent (Milli-Q water, 1% Tween-80 and 3% ethanol) (negative control). ST cross produced increase in total mutant spots in the individuals treated with 5, 10 or 20 mM of UA. HB cross produced spot frequencies in the concentration of 5 mM that were higher than the frequency for the same concentration in the ST cross. In the highest concentrations the result was negative, which means that the difference observed can be attributed, in part, to the high levels of P450, suggesting that increasing the metabolic capacity maximized the toxic effect of these doses. In the evaluation of carcinogenesis using the wts test, the results obtained for the same concentrations of UA show a positive result for the presence of tumors when compared to the negative control. We conclude that UA has recombinogenic, mutagenic and carcinogenic effects on somatic cells in D. melanogaster. The antioxidant and pro-oxidant properties of UA are likely to account for the present results.