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（由适用提供）：该赠款的最初特定目的1是在成年患者的临床临床（25 mg/kg/d）覆盖环境（25 mg/kg/d）的环境（25 mg/kg/d）的剂量范围内进行为期2天的暴露，然后才在经过良性肝脏病变（例如，cyst，cyst，celest，celeSt，celest）的开放性手术清除之前。邻近的健康组织将在病变中出现极好的病变，以分析谷胱甘肽转移酶（GSTZ1）的Zeta-1家族同工型，生物转化将DCA生物转化为乙二醇。 GSTZ1与酪氨酸分解代谢，甲基乙酸异构酶（MAAI）中的倒数第二酶相同。由于DCA在动物生活中抑制了这种酶，因此我们在人类的生命中也会这样做，从而导致血浆积累潜在的有毒酪氨酸代谢产物。但是，去年，UF外科医生对这些患者采用的标准护理方法从开放切口转变为囊肿的经皮引流和经皮去除大多数腺瘤，从而基本上消除了我们为此目标招募的受试者。根据，ES014617进行这种竞争性修订的目的是通过应用最先进的稳定的同位素动力学和动力学建模技术来纠正这种缺陷和基因型。这个目的测试了以下假设在健康成年人和临床暴露水平下，DCA对DCA对13C-酪氨酸动力学的抑制作用改变了13c-酪氨酸动力学，从而导致潜在的有毒酪氨酸代谢产物积累。我们进一步指出，抑制酪氨酸代谢的抑制作用将是具有GSTZ1/MAAI的KRT变体的受试者，DCA表现出很高的公里。全身蛋白质更新还将确定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）职业是生物医学中独特的地位，因为它作为潜在的环境毒素和治疗剂的意义。据信DCA可以抑制人类酪氨酸的代谢，并且它被认为与其潜在的环境和临床毒理学有关。该应用程序旨在确定DCA的定量影响，在环境和临床相关剂量上对人类酪氨酸代谢在基因型中的酪氨酸代谢，从而阐明了人类种群对不同DCA暴露水平的相关风险。