PHARMACOTOXICOLOGY OF TRICHLOROETHYLENE METABOLITES

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 中心，但不一定是研究者所在的机构。 本项目主要研究三氯乙烯的潜在有害代谢物二氯醋酸酯和水合氯醛的动力学、代谢和人体毒理学。 人类表现出MAAI的多态性，可能具有不同的动力学特性，以DCA。 反过来，人类单倍型变异可能会影响DCA？的动力学和毒理学。 将通过实现以下具体目标来检验这些假设：具体目标1：量化DCA在从环境到临床的暴露水平下对人肝MAAI和酪氨酸催化剂的影响。 该目的检验了以下假设：DCA对人肝细胞酪氨酸代谢总体上存在剂量依赖性效应，特别是对潜在肝毒性酪氨酸中间体的蓄积存在剂量依赖性效应，DCA以剂量依赖性方式抑制人体内肝脏MAAI表达，并且DCA、酪氨酸和/或其代谢产物与MAAI形成加合物。 具体目的2：建立人类MAAI单倍型与DCA和酪氨酸代谢的关系。这一目标测试的假设，MAAI单倍型确定，从而可以预测，剂量依赖性DCA动力学和生物转化和DCA？对酪氨酸代谢的影响。 具体目标3：确定健康成人中CH的体内动力学和生物转化以及CH和DCA相互影响？s代谢。 这一特定目标将检查三个假设CH在成人中代谢为DCA，CH通过DCA形成抑制其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 and chloral hydrate, potentially harmful metabolites of trichloroethylene. Humans exhibit polymorphisms of MAAI that may possess different kinetic properties toward DCA. In turn, 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 to clinical, 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.