BIOTRANSFORMATION AND PHARMACOKINETICS OF PYRETHROID INSECTICIDES

拟除虫菊酯类杀虫剂的生物转化和药代动力学

• 批准号: 7381816
• 负责人: MATTHEW K ROSS
• 金额: $ 16.46万
• 依托单位: MISSISSIPPI STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7381816
• 关键词: BIOTRANSFORMATION; PHARMACOKINETICS; PYRETHROID; INSECTICIDES

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. Hydrolytic and oxidative metabolism of pesticides contribute to their detoxification and excretion from exposed organisms. To enable development of physiologically based pharmacokinetic (PBPK) models that predict the disposition of pesticides in humans, the relative contribution of each biotransformation pathway to pesticide clearance requires quantitative characterization. The central hypothesis to be addressed in this project is that biotransformation of pyrethroid insecticides by carboxylesterases (CES) and cytochrome P450 (CYP) monooxygenases largely influence the pharmacokinetics of these pesticides. This study will investigate the role of rodent and human CES and CYP enzymes in the in vitro metabolism of permethrin and resmethrin (type I pyrethroids) and deltamethrin and cypermethrin (type II pyrethroids), which have not been investigated with respect to their human metabolism. Two major carboxylesterase isoforms have been identified in human liver and are termed hCE-1 and hCE-2. Specific aim #1 will involve investigating the substrate specificity of baculovirus-expressed hCE-1 and hCE-2 toward the pyrethroid compounds. Hydrolysis products of the pyrethroids will be detected and quantified by LC-MS methods. The kinetic parameters (Km, kcat) that describe the rates of cleavage of the ester-containing pyrethroids will be estimated for each isozyme to determine which compounds are most effectively hydrolyzed. Specific aim #2 will use recombinant human CYP isozymes and determine their substrate specificity and kinetic parameters toward the pyrethroid compounds. The catalytic efficiencies of the human CYP and CES enzymes will be directly compared so that the relative contribution of each enzyme to pyrethroid biotransformation can be determined. The in vitro toxicokinetic studies described in this proposal will complement and support in vivo studies in the development of PBPK models of pyrethroids. The knowledge of pesticide structure-activity relationships with respect to esterase and oxidative metabolism will be critical for predicting the metabolism and pharmacokinetics of pesticides in humans.

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子弹和调查员（PI）可能已经从其他NIH来源获得了主要资金，因此可以在其他清晰的条目中代表。列出的机构适用于该中心，这不一定是调查员的机构。农药的水解和氧化代谢有助于其排毒和排泄裸露的生物体。为了开发基于生理的药代动力学（PBPK）模型，以预测人类农药的处置，每个生物转化途径对农药清除的相对贡献都需要定量表征。该项目要解决的中心假设是，羧酸酯酶（CES）和细胞色素P450（CYP）单加氧化酶对拟除虫菊酯杀虫剂的生物转化很大程度上影响了这些农药的药代动力学。这项研究将研究啮齿动物和人类CES和CYP酶在苄氯菊酯和解酯蛋白（I型吡乙甲状腺功能亢进症）和甲甲酸酯以及二甲酸酯（II型甲状腺动物）（II型甲状腺素）的体外代谢中的作用。在人肝脏中已经鉴定出了两种主要的羧酸酯酶同工型，称为HCE-1和HCE-2。具体目标＃1将涉及研究杆状病毒表达的HCE-1和HCE-2对拟除虫菊酯化合物的底物特异性。将通过LC-MS方法检测和定量拟除虫菊酯的水解产物。对于每个同工酶，将估算描述含酯的拟除虫菊酯裂解速率的动力学参数（KM，KCAT），以确定哪些化合物最有效地水解了。特定的目标＃2将使用重组人CYP同工酶，并确定其底物的特异性和动力学参数对拟除虫菊酯化合物。将直接比较人CYP和CES酶的催化效率，以便可以确定每种酶对拟除虫菊酯生物转化的相对贡献。该提案中描述的体外毒理学研究将补充和支持拟除虫菊酯PBPK模型的体内研究。关于酯酶和氧化代谢的农药结构活性关系的知识对于预测人类农药的代谢和药代动力学至关重要。