Santos Lizandra Vitoria de Souza, Galvão Barbara Verena Dias, Souza Lays, Fernandes Andreia da Silva, Araujo-Lima Carlos Fernando, Felzenszwalb Israel
Department of Biophysics and Biometry, Rio de Janeiro State University, Rio de Janeiro, Brazil.
Department of Genetics and Molecular Biology, Federal University of Rio de Janeiro State, Rio de Janeiro, Brazil.
Toxicol Rep. 2024 Oct 2;13:101753. doi: 10.1016/j.toxrep.2024.101753. eCollection 2024 Dec.
Phenolic phytometabolites are promising bioactive compounds for management of genomic instability related diseases. Formononetin (FMN) and arbutin (ARB) are found in several plant sources. Our goal was to investigate the safety and efficacy of FMN and ARB using both standardized and alternative toxicogenetic methods. FMN and ARB were evaluated through the OECD'S guidelines No. 471 (Bacterial Reverse Mutation Test -/microsome) and No. 487 ( Mammalian Micronucleus Test - CBMN assay), accordingly to the mentioned recommendations. Also, antimutagenicity of FMN and ARB was assessed in . Typhimurium strains TA98, TA100 and TA1535, following pre-, co- and post- treatment protocols. Liver human lineages HepG2 and F C3H were assayed for cytotoxicity after exposure to FMN and ARB (24, 48 and 72 h) using WST-1 test. ARB showed no mutagenicity in the /microsome test under both metabolic conditions (in presence or absence of 4 % S9 mix), but FMN was cytotoxic to the TA97 and TA100 strains after metabolic activation. Under this same condition, FMN induced an increase in the mutagenic index of strain TA1535 at two of the highest tested concentrations. Even so, ARB and FMN exhibited protection against the induced alkylation of DNA in multiple action modes. In the antimutagenicity assay, FMN reached the maximum of 80 % of oxidative-provoked mutagenicity reduction in TA98 strain in co-treatment with known mutagen, besides 69 % of reduction in TA100 in the same exposure condition. ARB showed up to reduce induced mutagenicity in strains TA100 and TA1535, reaching percentages from 55 % to 100 % of antimutagenicity in all of the tested exposure models against alkylating agent. In the CBMN assay, no increase in micronuclei formation was observed. The results suggest that FMN and ARB prevent DNA from mutation using multi-targeted antimutagenic roles. Finally, our data suggests that FMN and ARB are not genotoxic and presented encouraging antimutagenicity action , being promising compounds for use in genomic instability-related diseases therapeutics.
酚类植物代谢产物是用于治疗基因组不稳定相关疾病的很有前景的生物活性化合物。在多种植物来源中都发现了芒柄花黄素（FMN）和熊果苷（ARB）。我们的目标是使用标准化和替代性毒理遗传学方法研究FMN和ARB的安全性和有效性。根据上述建议，通过经合组织第471号指南（细菌回复突变试验 - /微粒体）和第487号指南（哺乳动物微核试验 - CBMN试验）对FMN和ARB进行评估。此外，按照预处理、共处理和后处理方案，在鼠伤寒沙门氏菌TA98、TA100和TA1535菌株中评估FMN和ARB的抗诱变活性。使用WST - 1试验，检测人肝癌细胞系HepG2和小鼠胚胎成纤维细胞系FC3H在暴露于FMN和ARB（24、48和72小时）后的细胞毒性。在两种代谢条件下（存在或不存在4% S9混合物），ARB在/微粒体试验中均未显示出致突变性，但FMN在代谢活化后对TA97和TA100菌株具有细胞毒性。在相同条件下，FMN在两个最高测试浓度下诱导TA1535菌株的诱变指数增加。即便如此，ARB和FMN以多种作用模式对诱导的DNA烷基化表现出保护作用。在抗诱变试验中，在与已知诱变剂共同处理时，FMN在TA98菌株中使氧化诱发的诱变率降低达到最大值80%，在相同暴露条件下，在TA100菌株中降低69%。ARB在TA100和TA1535菌株中显示出降低诱导的诱变率，在所有针对烷基化剂的测试暴露模型中，抗诱变率达到55%至100%。在CBMN试验中，未观察到微核形成增加。结果表明，FMN和ARB通过多靶点抗诱变作用防止DNA突变。最后，我们的数据表明，FMN和ARB无基因毒性，并呈现出令人鼓舞的抗诱变作用，是用于治疗基因组不稳定相关疾病的有前景的化合物。
