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首页> 外文学位 >Application of quantitative structure-activity relationships to investigate xenobiotic cytotoxicity mechanisms in hepatocyte systems.
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Application of quantitative structure-activity relationships to investigate xenobiotic cytotoxicity mechanisms in hepatocyte systems.

机译：应用定量构效关系研究肝细胞系统中的异种细胞毒性机制。

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摘要

Hepatotoxicity is a serious adverse health effect caused by drugs and other chemical toxins generally detected in the later stages of drug development or in whole animal studies. Thus, development of screening approaches available for earlier identification of hepatotoxic molecules is necessary. A novel in vitro-in silico test system for the evaluation of the molecular mechanisms of xenobiotic toxicity in primary hepatocyte systems is presented here. It is well established that hepatocytes in vitro are most representative of hepatotoxicity in vivo, and are most useful for the determination of xenobiotic hepatotoxicity mechanisms at the molecular and cellular level. There is an on-going interest in Quantitative Structure-Activity Relationships (QSAR) in toxicology, as it can identify correlations between chemical structure and biological activity. QSAR can be used to evaluate the effects of metabolism and toxicity as many physicochemical descriptors reflect simple molecular properties that can provide insight into the physicochemical nature of the activity under consideration. QSARs were determined for hepatotoxicity of halobenzenes, p-benzoquinones, alpha,beta-unsaturated carbonyl compounds and nitroaromatics towards isolated hepatocytes. A molecular link was established for their proposed toxicity pathways. For example oxidative activation was linked to EHOMO (energy of the highest occupied molecular orbital) values and hydrophobicity (log P) of the chemicals, while reductive activation was linked with ELUMO (energy of the lowest molecular orbital) values and log P. Such relationships may thus be useful for predicting toxicity of other chemicals of the same mechanism of toxicity. Due to the complexity involved in the phenomena of hepatotoxicity, unravelling of structure-hepatotoxicity relationships is a complicated task. A conceptual framework for QSAR modeling is proposed that involves recognition of molecular initiating events as potential endpoints to improve the prediction potential of QSAR models. Acute toxicity of reactive chemicals could be based on an initial reaction with biomolecules, thus the theory of covalent binding reactivity was used to test this concept. Reactivity assays with thiol and amine surrogate nucleophiles were used to determine susceptibility to toxicity. The derived QSAR expressions suggested that covalent binding reactivity is a good correlate to hepatotoxicity, however only if electrophilicity was the main mechanism of toxicity.
机译：肝毒性是由药物和其他化学毒素引起的严重不良健康影响，通常在药物开发的后期或在整个动物研究中检测到。因此，需要开发可用于早期鉴定肝毒性分子的筛选方法。本文介绍了一种新型的体外计算机测试系统，用于评估原代肝细胞系统中异种生物毒性的分子机制。公认的是，体外肝细胞是体内肝毒性的最代表，并且在分子和细胞水平上对于确定异种生物的肝毒性机制最有用。毒理学中的定量结构-活性关系（QSAR）引起了人们的持续关注，因为它可以识别化学结构与生物活性之间的相关性。 QSAR可用于评估新陈代谢和毒性的影响，因为许多理化指标反映了简单的分子特性，可以洞悉所考虑活动的理化性质。确定了QSAR对卤代苯，对苯醌，α，β-不饱和羰基化合物和硝基芳香族化合物对分离的肝细胞的肝毒性。他们提出的毒性途径建立了分子联系。例如，氧化活化与化学物质的EHOMO（分子占据最高轨道的能量）值和疏水性（log P）相关，而还原活化与ELUMO（分子轨道具有最低的能量）值和log P相关。因此可能对预测具有相同毒性机制的其他化学品的毒性有用。由于涉及肝毒性现象的复杂性，弄清结构-肝毒性关系是一项复杂的任务。提出了用于QSAR建模的概念框架，该框架涉及将分子引发事件识别为潜在的终点，以提高QSAR模型的预测潜力。反应性化学品的急性毒性可能是基于与生物分子的初步反应，因此共价结合反应性理论被用来检验这一概念。用硫醇和胺替代亲核试剂进行反应性测定可确定对毒性的敏感性。推导的QSAR表达表明，共价结合反应性与肝毒性具有良好的相关性，但是只有亲电性是毒性的主要机制。

著录项

  • 作者

    Chan, Katherine.;

  • 作者单位

    University of Toronto (Canada).;

  • 授予单位 University of Toronto (Canada).;
  • 学科 Health Sciences Pharmacology.;Health Sciences Toxicology.
  • 学位 Ph.D.
  • 年度 2008
  • 页码 202 p.
  • 总页数 202
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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