The Impact of Genetic Variability on Human Susceptibility to Chlorpyrifos

描述（由申请人提供）：有机磷（OP）农药在世界范围内广泛使用，与OP化学战剂具有共同的机制。这些化合物抑制乙酰胆碱酯酶（AChE）和丁基胆碱酯酶（BChE）。这种抑制最重要的结果是神经递质乙酰胆碱（ACh）在神经元和肌肉突触中的积累，导致最初的过度刺激，随后是ACh受体的最终耗尽。毒死蜱（Chlorpyrifos， CPF）是世界上最常用的有机磷农药之一。与许多OP农药一样，CPF是一种前毒，必须主要通过肝脏中的细胞色素p450 （CYP）酶代谢为具有毒性活性的毒死蜱（CPF- o），才能发挥毒性作用。CPF-O是一种有效的胆碱酯酶（ChE）抑制剂。因此，CYP2B6（主要负责CPF生物活化的cypp酶）的遗传变异可能解释了毒性的个体间差异。假设人类CYP2B6已知的功能多态性将在CPF到CPF- o的生物活化动力学中表现出差异，并且个体的CYP2B6基因型将与其对CPF毒性的相对易感性相关。当前建议的目标是使用体外技术研究CYP2B6的不同流行亚型，并观察与正常的野生型酶相比，这些遗传变异的酶动力学的任何改变，并将这些动力学参数纳入基于生理的药代动力学/药效学（PBPK/PD）模型，以检查CYP2B6基因型与人类群体中作用和毒性的生物标志物之间的相关性。了解个体间变异性背后的机制有可能改善当前的风险评估工作，这些工作严重依赖于动物数据，并使用种群驱动的范式，其中包含不确定因素，用于解释个体之间知之甚少的变异性。此外，慢性暴露于CPF和其他OP化合物与多种神经和其他疾病的潜在关联尚不清楚。拟议的研究将确定在介导CPF毒性中起重要作用的遗传因素，澄清基因-环境相互作用，这将有助于继续努力调查CPF暴露与易感人群某些健康终点之间的联系。

DESCRIPTION (provided by applicant): Organophosphorus (OP) pesticides are extensively used worldwide and share a common mechanism with OP chemical warfare agents. These compounds inhibit the enzymes acetylcholinesterase (AChE) and butylrylcholinesterase (BChE). The most important result of this inhibition is the accumulation of the neurotransmitter acetylcholine (ACh) in neuronal and muscular synapses leading to an initial overstimulation, followed by eventual exhaustion of ACh receptors. Chlorpyrifos (CPF) is one of the most commonly used OP pesticides worldwide. Like many OP pesticides, CPF is a pro-poison and must be metabolized to the toxicologically active Chlorpyrifos oxon (CPF-O), primarily by cytochrome p450 (CYP) enzymes in the liver, to exert toxic effects. CPF-O is a potent cholinesterase (ChE) inhibitor. Genetic variability in CYP2B6, the CYP enzyme primarily responsible for CPF bioactivation may therefore account for interindividual variability in toxicity It is hypothesized that known functional polymorphisms in human CYP2B6 will exhibit variability in the kinetics for the bioactivation of CPF to CPF-O and that the CYP2B6 genotype of an individual will be related to their relative susceptibility to CPF toxicity. The objectives of the current proposal are to use in vitro techniques to study different prevalent isoforms of CYP2B6 and observe any altered enzyme kinetics of these genetic variants as compared to the normal, wild-type enzymes and to incorporate these kinetic parameters into a physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model to examine the correlation between CYP2B6 genotype and biomarkers of effect and toxicity in a human population. Understanding the mechanisms behind interindividual variability has the potential to improve current risk assessment efforts, which rely heavily on animal data and use population- driven paradigms with uncertainty factors used to account for poorly understood variability among individuals. In addition, the potential association of chronic exposure to CPF and other OP compounds with a multitude of neurological and other diseases is poorly understood. The proposed study will identify genetic factors that are important in mediating CPF toxicity, clarifying gene-environment interactions which will help the continuing efforts to investigate the link between CPF exposure and certain health endpoints in susceptible populations. PUBLIC HEALTH RELEVANCE: Chlorpyrifos (CPF) and other organophosphorus (OP) pesticides are heavily used worldwide and pose significant health risks, particularly in underdeveloped countries where personal protective equipment (PPE) and other safety regulations may be lacking. Identification and protection of the most susceptible populations can improve preventative health care and reduce risks. Knowledge of underlying biological mechanisms of interindividual variability is needed to identify those individuals most at risk for CPF toxicity.