PDF(Pubmed)
Abstract：
Difenoconazole is a chemical entity containing two chiral centers and having four stereoisomers: (2R,4R)-, (2R,4S)-, (2S,4R)- and (2S,4S)-difenoconazole, the marketed product containing a mixture of these isomers. Residues of difenoconazole have been identified in many agricultural products and drinking water. A computational approach has been used to evaluate the toxicological effects of the difenoconazole stereoisomers on humans. It integrates predictions of absorption, distribution, metabolism, excretion and toxicity (ADMET) profiles, prediction of metabolism sites, and assessment of the interactions of the difenoconazole stereoisomers with human cytochromes, nuclear receptors and plasma proteins by molecular docking. Several toxicological effects have been identified for all the difenoconazole stereoisomers: high plasma protein binding, inhibition of cytochromes, possible hepatotoxicity, neurotoxicity, mutagenicity, skin sensitization potential, moderate potential to produce endocrine disrupting effects. There were small differences in the predicted probabilities of producing various biological effects between the distinct stereoisomers of difenoconazole. Furthermore, there were significant differences between the interacting energies of the difenoconazole stereoisomers with plasma proteins and human cytochromes, the spectra of the hydrogen bonds and aromatic donor-acceptor interactions being quite distinct. Some distinguishing results have been obtained for the (2S,4S)-difenoconazole: it registered the highest value for clearance, exposed reasonable probabilities to produce cardiotoxicity and carcinogenicity and negatively affected numerous nuclear receptors.
摘要：
苯醚环唑是一种含有两个手性中心并具有四个立体异构体的化学实体：（2R，4R)-,(2R,4S)-,(2S,4R)-和(2S，4S)-苯醚甲环唑,含有这些异构体混合物的市售产品。苯醚甲环唑的残留已在许多农产品和饮用水中被发现。一种计算方法已用于评估苯醚甲环唑立体异构体对人类的毒理学影响。它整合了吸收的预测，分布，新陈代谢，排泄和毒性(ADMET)概况，预测代谢位点，并评估苯醚甲环唑立体异构体与人细胞色素的相互作用，核受体和血浆蛋白通过分子对接。已经确定了所有苯醚甲环唑立体异构体的几种毒理学作用：高血浆蛋白结合，抑制细胞色素，可能的肝毒性，神经毒性，致突变性,皮肤致敏潜能，产生内分泌干扰作用的中等潜力。苯醚甲环唑的不同立体异构体之间产生各种生物学效应的预测概率差异很小。此外，苯醚甲环唑立体异构体与血浆蛋白和人细胞色素的相互作用能之间存在显着差异，氢键和芳香供体-受体相互作用的光谱非常不同。对于(2S，4S）-苯醚甲环唑：它记录了最高的清除率值，暴露产生心脏毒性和致癌性的合理概率，并对许多核受体产生负面影响。
