The Impact of Genetic Variability on Human Susceptibility to Chlorpyrifos

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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.