PHARMACOTOXICOLOGY OF TRICHLOROETHYLENE METABOLITES

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 本项目主要研究三氯乙烯-三氯乙烯的潜在有害代谢物二氯乙酸酯-DCA和水合氯醛-CH的动力学、代谢和人体毒理学。人类表现出MAAI的多态，这种多态可能具有不同的动力学特性。人类单倍型变异可能会影响DCA的动力学和毒理学。这些假设将通过实现以下具体目标来检验： 具体目标1：量化从环境暴露水平到临床暴露水平的DCA对人体肝脏MAAI和酪氨酸分解代谢的影响。这一目的验证了以下假设：DCA对人肝细胞酪氨酸代谢，特别是对潜在的肝毒性酪氨酸中间体的积累存在剂量依赖性的影响；DCA以剂量依赖的方式抑制人体内肝脏MAAI的表达；DCA、酪氨酸和/或它们的代谢产物与MAAI形成加合物。 具体目的2：建立人MAAI单倍型与DCA和酪氨酸代谢的关系。这一目的检验了MAAI单倍型决定的假设，从而可以预测：剂量依赖的DCA动力学和生物转化以及DCA对酪氨酸代谢的影响。 具体目标3：测定CH在健康成人体内的代谢动力学和生物转化，以及CH和DCA对彼此代谢的影响。这个特定的目标将检验三个假设：CH在成人体内代谢成DCA；CH通过DCA的形成抑制自身的代谢和酪氨酸的代谢；这些影响取决于暴露水平，而不是性别。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This project focuses on the kinetics, metabolism and human toxicology of dichloroacetate-DCA and chloral hydrate-CH, potentially harmful metabolites of trichloroethylene-TCE. Humans exhibit polymorphisms of MAAI that may possess different kinetic properties toward DCA. Human haplotype variability may influence DCA's kinetics and toxicology. These hypotheses will be tested by accomplishing the following Specific Aims: Specific Aim 1: Quantify the influence of DCA, at exposure levels ranging from environmental, ¿g/kg/d to clinical, mg/kg/d, on human liver MAAI and tyrosine catabolism. This aim tests the hypotheses that: there is a dose-dependent effect of DCA on human hepatocellular tyrosine metabolism in general and on the accumulation of potentially hepatotoxic tyrosine intermediates in particular; DCA inhibits hepatic MAAI expression in vivo in humans in a dose-dependent manner; and DCA, tyrosine and/or their metabolites form adducts with MAAI. Specific Aim 2: Establish the relationship between human MAAI haplotype and DCA and tyrosine metabolism. This aim tests the postulates that MAAI haplotype determines, and thus can predict: dose-dependent DCA kinetics and biotransformation and DCA's effects on tyrosine metabolism. Specific Aim 3: Determine the in vivo kinetics and biotransformation of CH in healthy adults and the influence of CH and DCA on each other's metabolism. This specific aim will examine three postulates: CH is metabolized in adults to DCA; CH, via DCA formation, inhibits its own metabolism and that of tyrosine; and these effects are dependent upon exposure level but not upon gender.