PAEs对线粒体转录因子A蛋白相对表达量的影响及3D-QSAR模型构建

Effect of PAEs on Relative Expression of Mitochondrial Transcription Factor A Protein and Construction of 3D-QSAR Model

邻苯二甲酸酯类化合物(phthalate esters,PAEs)是一种内分泌干扰物质,因具有增塑性而被广泛使用,但其对环境产生持久性污染。选取6种PAEs作为研究对象,基于相似性指数分析(comparative molecular similarity indices analysis,CoMSIA)方法探究PAEs分子结构对HepG2细胞中线粒体转录因子A(mitochondrial transcription factor A,Tfam)蛋白相对表达量的影响。结果显示,当PAEs的浓度为1000μmol·L^(-1)时,降低HepG2细胞中Tfam的表达,其中邻苯二甲酸二正丁酯(dibutyl phthalate,DBP)和邻苯二甲酸二正辛酯(di-n-octyl phthalate,DNOP)对Tfam蛋白相对表达量的影响较大。在3D-QSAR模型中,非交叉验证相关系数(R^(2))为0.983,交叉验证系数(Q^(2))为0.508,结合外部验证及Williams图,说明该模型有较好的稳定性及预测性。基于CoMSIA轮廓图,揭示了在支链引入负电基团、疏水基团及增加氢键受体可提高Tfam蛋白相对表达量,减弱PAEs导致的HepG2细胞线粒体生物发生障碍,进一步降低PAEs对HepG2细胞的线粒体毒性。

Phthalate esters(PAEs)are typical environmental endocrine disruptors.Because of their plasticity,PAEs are widely used in different commercial products,which will cause environmental pollution.Six PAEs were chosen as the analytical objects,comparative molecular similarity indices analysis(CoMSIA)method was used to explore the influence of PAEs molecular structure on the relative expression of mitochondrial transcription factor A(Tfam)protein in HepG2 cells.The results showed that when the concentration of PAEs was 1000μmol·L^(-1),the relative expressions of Tfam proteins were decreased in HepG2 cells,of which DBP and DNOP had greater influences on the relative expressions of Tfam protein.The non-cross validation coefficient(R^(2))of the 3D-QSAR model established in this experiment was 0.983,and the cross validation coefficient(Q^(2))was 0.508.Combined with the external validation and Williams diagram,it was shown that the model had good stability and predictability.Based on the CoMSIA profile,it was revealed that the introduction of negative and hydrophobic groups into the branch chain and the increase of hydrogen bond acceptor promoted the relative expression of Tfam protein,weakened the mitochondrial biogenetic dysfunction of HepG2 cells induced by PAEs,and further reduced the mitochondrial toxicity of PAEs to HepG2 cells.