PREDICTION OF METABOLIC PATHWAYS FOR TOXIC CHEMICALS

毒物学家面临的一个主要障碍是定量评估。 环境化学品、食品添加剂和药物的毒性风险 一个物种(例如，人类)基于另一个物种的毒理学研究 物种。推断中的错误常常是由物种差异引起的 在毒物的新陈代谢中。然而，最近在这方面的进展 哺乳动物混合功能氧化酶(MFO)酶系统研究 主要毒物代谢酶，提示某些物种间 催化作用的共性。这项研究将采用 区域选择性代谢MFO底物以检验假设 对其他化学物质的抑制能力的定量知识 试验底物的代谢可以用来预测代谢的命运。 一种以前没有测试过的化学物质。华法林对映体和乙基吗啡 将被用作肝微粒体MFO酶的测试底物 取自大鼠和小鼠。选择性诱导和销毁方法 将用于分离区域选择性不同的MFO酶。刚硬 华法林的类似物将作为MFO酶抑制剂进行测试。一个 定量构效关系(QSAR)模型关联 对互变异构体、立体异构体、亲脂性和 将开发和检查物种间的电子特性 不同之处。利用定量构效关系模型预测化合物的抑制能力 另一种类似物，其代谢命运将被确定和关联 它的抑制能力。该方法有可能扩展到其他 未经测试的化学品作为改进毒理学风险评估的一种手段。

A major obstacle confronting toxicologists is the quantitative assessment of risk of toxicity by environmental chemicals, food additives and drugs in one species (e.g., humans) based on toxicological studies in another species. Errors in extrapolation frequently arise from species differences in the metabolism of the toxicant. Nevertheless, recent progress in studies of the mammalian mixed-function oxidase (MFO) enzyme system, the primary toxicant metabolizing enzymes, suggest certain interspecies commonalities in catalytic function. This study will employ regioselectively metabolized MFO substrates to test the hypothesis that quantitative knowledge of the ability of other chemicals to inhibit the metabolism of the test substrates may be used to predict the metabolic fate of a previously untested chemical. Warfarin enantiomers and ethylmorphine will be used as test substrates with hepatic microsomal MFO enzymes obtained from rats and mice. Selective induction and destruction methods will be used to segregate regioselectively distinct MFO enzymes. Rigid analogs of warfarin will be tested as MFO enzyme inhibitors. A quantitative structure-activity relationship (QSAR) model relating inhibitory power to tautomeric form, stereoisomer, lipophilicity and electronic properties will be developed and examined for interspecies differences. The QSAR model will be used to predict the inhibitory ability of another analog, whose metabolic fate will then be determined and related to its inhibitory power. The method can potentially be extended to other untested chemicals as a means of improving toxicological risk assessment.