Pharmacotoxicology of Trichloroethylene Metabolites

三氯乙烯代谢物的药理学

• 批准号: 7812724
• 负责人: Peter Wallace Stacpoole
• 金额: $ 37.81万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-17 至 2012-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7812724
• 关键词: Address; Adult; Adverse effects; Analytical Chemistry; Animals; Arts; Award; Benign; Biochemical; Blood; Caring; Catabolism; Chemicals; Child; Chloral Hydrate; Chronic; Clinical; Clinical Research; Cyst; Data; Dichloroacetate; Dose; Drainage procedure; Enzymes; Excision; Exhibits; Family; Gender; Gene Frequency; Genetic; Genetic Polymorphism; Genotype; Glutathione S-Transferase; Glyoxylates; Grant; Haplotypes; Hepatic; Human; Investigation; Kinetics; Lesion; Liver; Maleylacetoacetate isomerase; Mediating; Metabolic Biotransformation; Metabolism; Modeling; Oral; Oral cavity; Patients; Pharmacogenetics; Plasma; Population; Property; Protein Isoforms; Research; Risk; Surgeon; Surgical incisions; Techniques; Testing; Therapeutic Agents; Tissues; Toxic Environmental Substances; Toxic effect; Toxicology; Trichloroethylene; Tyrosine; Tyrosine Metabolism Pathway; Variant; Woman; adduct; adenoma; clinical toxicology; clinically relevant; dechlorination; glyoxylate; in vivo; insight; men; protein degradation; public health relevance; research study; stable isotope; urinary

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.

描述（由申请人提供）：本次资助的最初具体目标 1 是在成年患者接受开放手术切除良性肝脏病变（例如囊肿、腺瘤）之前，进行为期 2 天的口服 DCA 暴露，覆盖环境（2.5 µg/kg/d）-临床（25 mg/kg/d）剂量范围。切除病灶的邻近健康组织将用于分析谷胱甘肽转移酶 (GSTz1) 的 zeta-1 家族亚型，该酶将 DCA 生物转化为乙醛酸。 GSTz1 与酪氨酸分解代谢中的倒数第二个酶马来酰乙酰乙酸异构酶 (MAAI) 相同。由于 DCA 会抑制动物肝脏中的这种酶，因此我们推测它也会在人类肝脏中发挥作用，导致潜在有毒酪氨酸代谢物在血浆中积聚。然而，去年，佛罗里达大学外科医生对这些患者采用的标准护理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受试者的情况。因此，ES014617 竞争性修订的目的是通过应用 PI 及其同事在授予 R01 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弥补这一缺陷，以实现以下目标： 具体目标 4：量化 DCA 对人类酪氨酸代谢及其自身与剂量相关的生物转化的影响 和基因型。该目的测试了以下假设：DCA 抑制 GSTz1/MAAI 会改变健康成人在环境和临床暴露水平下的 13C-酪氨酸动力学，导致潜在有毒酪氨酸代谢物的积累。我们进一步假设，在携带 GSTz1/MAAI 的 KRT 变体的受试者中，酪氨酸代谢的抑制将是最大的，而 DCA 对此表现出高 Km。还将确定全身蛋白质周转率，以帮助解释酪氨酸动力学数据。 公共健康相关性：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 被认为会抑制人类酪氨酸代谢，这被认为受到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施用的 DCA 对人类酪氨酸代谢（与基因型相关）的定量影响，从而阐明人群对不同 DCA 暴露水平的相关风险。