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首页> 外文期刊>Toxicology Letters: An International Journal Providing a Forum for Original and Pertinent Contributions in Toxicology Research >Prediction of pharmacokinetic and toxicological parameters of a 4-phenylcoumarin isolated from geopropolis: In silico and in vitro approaches
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Prediction of pharmacokinetic and toxicological parameters of a 4-phenylcoumarin isolated from geopropolis: In silico and in vitro approaches

机译：从地理高波利菌中分离的4-苯基伞林的药代动力学和毒理学参数的预测：在硅和体外方法中

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In silico and in vitro methodologies have been used as important tools in the drug discovery process, including from natural sources. The aim of this study was to predict pharmacokinetic and toxicity (ADME/Tox) properties of a coumarin isolated from geopropolis using in silico and in vitro approaches. Cinnamoyloxy-mammeisin (CNM) isolated from Brazilian M. scutellaris geopropolis was evaluated for its pharmacokinetic parameters by in silico models (ACD/Percepta (TM) and MetaDrug (TM) software). Genotoxicity was assessed by in vitro DNA damage signaling PCR array. CNM did not pass all parameters of Lipinski's rule of five, with a predicted low oral bioavailability and high plasma protein binding, but with good predicted blood brain barrier penetration. CNM was predicted to show low affinity to cytochrome P450 family members. Furthermore, the predicted Ames test indicated potential mutagenicity of CNM. Also, the probability of toxicity for organs and tissues was classified as moderate and high for liver and kidney, and moderate and low for skin and eye irritation, respectively. The PCR array analysis showed that CNM significantly upregulated about 7% of all DNA damage-related genes. By exploring the biological function of these genes, it was found that the predicted CNM genotoxicity is likely to be mediated by apoptosis. The predicted ADME/Tox profile suggests that external use of CNM may be preferable to systemic exposure, while its genotoxicity was characterized by the upregulation of apoptosis-related genes after treatment. The combined use of in silico and in vitro approaches to evaluate these parameters generated useful hypotheses to guide further preclinical studies. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
机译：在硅和体外方法中已被用作药物发现过程中的重要工具，包括来自天然来源。本研究的目的是预测在硅和体外方法中使用来自地质波利波利的香豆素的药代动力学和毒性（ADME / TOX）性质。通过在硅模型（ACD / PERCEPTA（TM）和METDRUG（TM）软件中，评估从巴西M.Scutellaris Geocropolis中分离的肉桂酰辛-Mammeisin（CNM）。通过体外DNA损伤来评估基因毒性信号PCR阵列。 CNM没有通过Lipinski规则的所有参数，具有预测的低口服生物利用度和高血浆蛋白质结合，但具有良好的预测血脑屏障渗透。预计CNM将显示对细胞色素P450家族成员的低亲和力。此外，预测的AME测试表明CNM的潜在致突变性。而且，对于肝脏和肾脏的毒性和组织的毒性概率分别被归类为中等和高，分别适中和低，用于皮肤和眼睛刺激。 PCR阵列分析表明，CNM显着上调了所有DNA损伤相关基因的约7％。通过探索这些基因的生物学功能，发现预测的CNM基因毒性可能是通过凋亡介导的。预测的ADME / TOX型谱表明，CNM的外部使用对于系统性暴露可能是优选的，而其遗传毒性的特征在于治疗后的凋亡相关基因的上调。在硅和体外方法中的结合使用来评估这些参数产生有用的假设，以引导进一步的临床前研究。 （c）2016 Elsevier Ireland Ltd.保留所有权利。

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