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。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。农药的水解和氧化代谢有助于其解毒和从暴露的生物体中排出。为了能够开发基于生理学的药代动力学（PBPK）模型，预测农药在人体内的处置，每种生物转化途径对农药清除的相对贡献需要定量表征。拟除虫菊酯类杀虫剂的羧酸酯酶和细胞色素P450单加氧酶的生物转化作用在很大程度上影响了这些杀虫剂的药代动力学。本研究将研究啮齿动物和人CES和酶在氯菊酯和苄氯菊酯（I型拟除虫菊酯）以及溴氰菊酯和氯氰菊酯（II型拟除虫菊酯）体外代谢中的作用，尚未研究其人体代谢。在人类肝脏中已经鉴定出两种主要的羧酸酯酶同种型，并将其称为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。拟除虫菊酯的水解产物将通过LC-MS方法进行检测和定量。将估计每种同工酶描述含酯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。具体目标#2将使用重组人β-同工酶，并确定其对拟除虫菊酯化合物的底物特异性和动力学参数。将直接比较人源化酶和CES酶的催化效率，以便确定每种酶对拟除虫菊酯生物转化的相对贡献。本提案中描述的体外毒代动力学研究将补充和支持拟除虫菊酯PBPK模型开发中的体内研究。农药酯酶和氧化代谢的构效关系的知识将是至关重要的预测代谢和农药在人体内的药代动力学。