Avaliação citotóxica, mutagênica, carcinogênica e in silico do ácido betulínico

• Ano de defesa: 2022
• Autor(a) principal: Oliveira, Victor Constante
• Tipo de documento: Tese
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Universidade Federal de Uberlândia; Brasil; Programa de Pós-graduação em Genética e Bioquímica
• Palavras-chave em Português: Antigenotoxicidade; Antimutagenicidade; Anticarcinogenicidade; Citocromo P450; Teste de micronúcleo; Teste de mutação e recombinação somática; Teste de tumor epitelial; Efeito apoptótico; Docking molecular; CNPQ::CIENCIAS BIOLOGICAS::GENETICA; Genética; Carcinogênese; Agentes antineoplásicos; Ácidos - Deposição
• Link de acesso: https://repositorio.ufu.br/handle/123456789/35015; http://doi.org/10.14393/ufu.te.2022.5004

Betulinic acid (AB) is a pentacyclic triterpenoid found in several plant species. Here, we examine the genotoxicity and mutagenicity of BA alone or in combination with URE using the mouse bone marrow cell micronucleus assay and the somatic mutation and recombination test in Drosophila melanogaster. The findings revealed that the isolated AB was not genotoxic but reduced the frequency of micronuclei when compared to the positive control. No significant differences in cytotoxicity were observed. Biochemical analyzes did not show significant differences for hepatic (AST and ALT) or renal (creatinine and urea) function parameters, indicating the absence of hepatotoxic and nephrotoxic effects. AB alone did not increase the frequency of mutant spots but reduced the total frequency of mutant spots when co-administered with URE in both the ST and HB crosses. In addition, AB reduced the recombinogenic effect of URE at the highest concentrations of both crosses. We also evaluated AB alone for carcinogenicity and combined with DXR (0.4 mM) for anticarcinogenicity, using the Epithelial Tumor Test (ETT) in Drosophila melanogaster. AB alone did not significantly increase tumor frequency but was able to reduce overall tumor frequency when co-administered with DXR at all concentrations. MCF10A (non-tumorigenic) and MDA-MB-231 (tumorigenic) triple-negative mammary cells were treated with AB at different concentrations for 24 and 48 h and cell viability was evaluated by the MTT tetrazolium salt colorimetric assay. AB reduced the cell viability of MCF10A and MDA-MB-231 cells in a concentration-dependent manner compared to control (untreated cells). However, the cytotoxic effect of AB was more significant after 48 hours, where the reduction in growth viability was more efficient in MDA-MB-231 cells. The LDH release assay was used to measure the cell damage caused by AB. It was observed that there was no significant difference in LDH release when comparing untreated and AB-treated cells. To elucidate some of the ways in which AB works, we performed an in silico molecular docking analysis. The result of the search for the most likely targets of AB revealed that SUMO (SAE1/UBA2), DNA POLβ and AKR1B10 had the highest percentages of chance of being targets of the AB ligand. In conclusion, under experimental conditions, BA has modulatory effects on URE-induced genotoxicity in mice as well as in D. melanogaster somatic cells. our data suggest that BA can modulate the carcinogenic effect of DXR, inducing damaged cells to apoptosis through different pathways involving SUMO proteins (SAE1 and UBA2), DNA POLβ and AKR1B10. New studies must be carried out using other reference carcinogens and different organisms to confirm the use of this compound in the production of new drugs.