Hydrolytic enzymes in the metabolism of toxins

毒素代谢中的水解酶

• 批准号: 8210927
• 负责人: BRUCE D HAMMOCK
• 金额: $ 38.7万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 1980
• 资助国家: 美国
• 起止时间: 1980-12-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8210927
• 关键词: Acids; Acute; Address; Agonist; Allosteric Regulation; Angiotensins; Arachidonic Acids; Biochemical; Biochemistry; Biological; Biological Markers; Biology; Blood Pressure; Cardiovascular Diseases; Chemicals; Clinical Trials; Complement; Cytochromes; Development; Diet; Dietary Fats; Disease; Drug effect disorder; Endocannabinoids; Environmental Pollution; Environmental Risk Factor; Enzyme Kinetics; Enzymes; Epoxide hydrolase; Epoxy Compounds; Evaluation; Exposure to; Family; Fatty Acids; Goals; Grant; Health; Herbicides; Human; Hydrolase; Hydrolysis; Hypertension; Inflammation; Inflammatory Response; Kinetics; Knockout Mice; Knowledge; Lipids; Mediation; Mediator of activation protein; Metabolism; Methods; Microsomal Epoxide Hydrolase; Modeling; Nutraceutical; Nutritional status; PTGS2 gene; Pain; Pathway interactions; Pattern; Peptides; Perception; Peroxisome Proliferator-Activated Receptors; Pesticides; Pharmaceutical Preparations; Pharmacologic Substance; Physiological; Plasma; Play; Population; Regulation; Reporting; Risk; Role; Self Care; Series; Single Nucleotide Polymorphism; Site; Soaps; Structure; System; Testing; Toxic effect; Urea; Variant; Water; Work; X-Ray Crystallography; Xenobiotic Metabolism; Xenobiotics; analytical tool; antimicrobial; arachidonate; base; blood pressure regulation; environmental chemical; human CYP2B6 protein; human disease; improved; inhibitor/antagonist; metabolic abnormality assessment; metabolomics; novel; tool; toxin metabolism; triclocarban

DESCRIPTION (provided by applicant): Evaluation of the risk of foreign compounds depends upon understanding the enzymes involved their degradation. A set of under-studied metabolic enzymes include the epoxide hydrolases in the ?/?-hydrolase fold family. These enzymes degrade epoxides by adding water. Some epoxides are reactive and highly mutagenic, and epoxides are commonly formed as metabolically labile functionalities by cytochrome P450s from variety of environmental chemicals. Not only are the levels of epoxide hydrolases variable in the human population, but they can be inhibited or induced by environmental chemicals and drugs. A central hypothesis is that epoxide hydrolases also have endogenous roles. We have established that the soluble epoxide hydrolase also acts on epoxides of arachidonic acid. These are key regulatory lipids. In fact, an inhibitor of the soluble epoxide hydrolase we made during the last grant period is in clinical trials to treat hypertension. Because the soluble epoxide hydrolase is involved in the regulation of blood pressure, inflammation and pain, it additionally represents a novel target for the action of xenobiotics. Similarly, inhibition of the microsomal epoxide hydrolase leads to acute xenobiotic toxicity. The knowledge of ?/?-fold enzymes will be expanded by completing two major objectives, and the tools developed here are critical to test a series of hypotheses regarding the endogenous role of the soluble epoxide hydrolase. Objective I addresses the structure and fundamental biochemistry of epoxide hydrolases with a major emphasis on the less studied soluble form. Objective II continues the development of a metabolomic profiling system to examine biologically active lipids in the arachidonate cascade and related pathways. Using this analytical platform as well as potent inhibitors and inducers of the enzyme, the role of the soluble epoxide hydrolase as a key enzyme in the arachidonate cascade and thus regulation of inflammation and pain will be evaluated. Along with 15% of the world's pharmaceuticals, common herbicides and personal care products are also known to act on the arachidonate cascade. For example we have found the common soap anti microbial, triclocarban, is a potent inhibitor of the soluble epoxide hydrolase and the endogenous peptide angiotensin along with PPAR? agonists are inducers. By addressing our objectives, knowledge will be expanded on the biochemistry and role in xenobiotic metabolism of epoxide hydrolases. The hypothesis of endogenous roles for epoxide hydrolases will be tested and the arachidonate cascade evaluated as a site of action for xenobiotics and nutraceuticals. PUBLIC HEALTH RELEVANCE: Epoxide hydrolase enzymes protect us against many environmental chemicals, and some of them also function to regulate our blood pressure, inflammation and pain. This study will identify new epoxide hydrolase targets for the action of drugs and nutraceuticals to improve health. This knowledge will also predict risk from environmental chemicals that increase or decrease the levels of epoxide hydrolases.

描述（由申请人提供）：外来化合物风险的评估取决于对参与其降解的酶的了解。一组正在研究的代谢酶包括β-水解酶折叠家族中的环氧化物水解酶。这些酶通过添加水来降解环氧化物。一些环氧化物具有反应性和高度诱变性，环氧化物通常是由各种环境化学物质中的细胞色素 P450 形成的代谢不稳定功能。环氧化物水解酶的水平不仅在人群中存在差异，而且还可能受到环境化学物质和药物的抑制或诱导。一个中心假设是环氧化物水解酶也具有内源性作用。我们已经确定可溶性环氧化物水解酶也作用于花生四烯酸的环氧化物。这些是关键的调节脂质。事实上，我们在上次资助期间制造的可溶性环氧化物水解酶抑制剂正在进行治疗高血压的临床试验。由于可溶性环氧化物水解酶参与血压、炎症和疼痛的调节，因此它还代表了异生素作用的新靶点。类似地，抑制微粒体环氧化物水解酶会导致急性外源性毒性。通过完成两个主要目标，将扩展 β-折叠酶的知识，并且这里开发的工具对于测试有关可溶性环氧化物水解酶的内源性作用的一系列假设至关重要。目标 I 阐述环氧化物水解酶的结构和基本生物化学，重点关注研究较少的可溶形式。目标 II 继续开发代谢组学分析系统，以检查花生四烯酸级联和相关途径中的生物活性脂质。使用该分析平台以及该酶的有效抑制剂和诱导剂，将评估可溶性环氧化物水解酶作为花生四烯酸级联中关键酶的作用，从而评估炎症和疼痛的调节。众所周知，除了世界上 15% 的药品之外，常见的除草剂和个人护理产品也会对花生四烯酸级联产生作用。例如，我们发现常见的肥皂抗微生物剂三氯卡班是可溶性环氧化物水解酶和内源性肽血管紧张素以及 PPAR 的有效抑制剂？激动剂是诱导剂。通过实现我们的目标，将扩展关于环氧化物水解酶的生物化学和外源代谢中的作用的知识。将测试环氧化物水解酶内源性作用的假设，并评估花生四烯酸级联作为异生素和营养保健品的作用位点。公共卫生相关性：环氧化物水解酶可以保护我们免受许多环境化学物质的侵害，其中一些还可以调节我们的血压、炎症和疼痛。这项研究将确定新的环氧化物水解酶靶标，以促进药物和营养保健品改善健康。这些知识还将预测增加或减少环氧化物水解酶水平的环境化学物质的风险。