Pharmacotoxicology of Trichloroethylene Metabolites

描述（由申请人提供）：该资助的最初具体目标1是在成人患者接受良性肝脏病变（例如，囊肿、腺瘤）。切除病变的邻近健康组织将用于分析谷胱甘肽转移酶（GSTz 1）的zeta-1家族亚型，该酶将DCA生物转化为乙醛酸。GSTz 1与酪氨酸催化剂中的倒数第二个酶，马来酰乙酰乙酸异构酶（MAAI）相同。由于DCA抑制动物肝脏中的这种酶，我们假设它也会在人类肝脏中这样做，导致潜在毒性酪氨酸代谢物的血浆蓄积。然而，去年UF外科医生应用于这些患者的标准治疗方法从开放切口改为经皮囊肿引流和经皮切除大多数腺瘤，从而基本上消除了我们为此目的招募的受试者。因此，ES 014617的本竞争修订版旨在通过应用PI及其同事在授予本R 01之前和之后开发的最先进的稳定同位素动力学和动力学建模技术来纠正这一缺陷，以实现以下目标：具体目标4：量化DCA对人体酪氨酸代谢及其自身生物转化的影响（与剂量和基因型相关）。该目的测试了以下假设：DCA抑制GSTz 1/MAAI改变了健康成人在环境和临床暴露水平下的13 C-酪氨酸动力学，导致潜在毒性酪氨酸代谢产物的蓄积。我们进一步假设，酪氨酸代谢的抑制作用在携带GSTz 1/MAAI KRT变异体的受试者中最大，其中DCA表现出高Km。还将测定全身蛋白质周转，以帮助解释酪氨酸动力学数据。 公共卫生相关性：二氯乙酸（DCA）在生物医学中占有独特的地位，因为它既是一种潜在的环境毒素，又是一种治疗剂。DCA被认为抑制人类酪氨酸代谢，这被认为是遗传影响，并与其潜在的环境和临床毒理学有关。本申请旨在确定以环境和临床相关剂量给予的DCA对人类酪氨酸代谢的定量影响（与基因型相关），从而阐明人群对不同DCA暴露水平的相关风险。

DESCRIPTION (provided by applicant): The original Specific Aim 1 of this grant was to conduct a 2-day exposure of oral DCA covering the environmental (2.5 ¿g/kg/d)-clinical (25 mg/kg/d) dose range in adult patients just prior to them undergoing open surgical removal of a benign liver lesion (e.g., cyst, adenoma). Adjacent healthy tissue excised with the lesion would be taken for analysis of the zeta-1 family isoform of glutathione transferase (GSTz1), which biotransforms DCA to glyoxylate. GSTz1 is identical to the penultimate enzyme in tyrosine catabolism, maleylacetoacetate isomerase (MAAI). Because DCA inhibits this enzyme in animal livers, we postulated it would also do so in human livers, leading to the plasma accumulation of potentially toxic tyrosine metabolites. However, last year the standard-of-care approach applied by UF surgeons to these patients changed from open incisions to percutaneous drainage of cysts and percutaneous removal of most adenomas, thereby essentially eliminating our recruitment of subjects for this Aim. Accordingly, the purpose of this Competitive Revision of ES014617 is to redress this deficiency by applying state-of-the-art stable isotope kinetics and kinetic modeling techniques developed by the PI and his colleagues prior to and since the awarding of this R01 to accomplish the following aim: Specific Aim 4: Quantify the effects of DCA on human tyrosine metabolism and on its own biotransformation in relation to dose and genotype. This aim tests the postulate that inhibition of GSTz1/MAAI by DCA alters 13C-tyrosine kinetics in healthy adults at both environmental and clinical exposure levels, resulting in accumulation of potentially toxic tyrosine metabolites. We further postulate that inhibition of tyrosine metabolism will be greatest in subjects who harbor the KRT variant for GSTz1/MAAI for which DCA exhibits a high Km. Whole body protein turnover will also be determined to aid in the interpretation of the tyrosine kinetic data. PUBLIC HEALTH RELEVANCE: Dichloroacetate (DCA) occupies a unique place in biomedicine because of its significance as both a potential environmental toxin and a therapeutic agent. DCA is believed to inhibit human tyrosine metabolism and this it thought to be genetically influenced and related to its potential environmental and clinical toxicology. This application seeks to determine the quantitative impact of DCA, administered at both environmentally and clinically relevant doses, on tyrosine metabolism in human in relation to genotype, thereby elucidating the relevant risk of human populations to different DCA exposure levels.