Pacific Northwest National Laboratory, Center for Biological Monitoring and Modeling, 902 Battelle Boulevard, Richland, WA 99352, USA.
Chem Biol Interact. 2010 Mar 30;184(3):449-57. doi: 10.1016/j.cbi.2010.01.024. Epub 2010 Jan 25.
Routine use of tobacco products may modify physiological and metabolic functions, including drug metabolizing enzymes, which may impact the pharmacokinetics of environmental contaminants. Chlorpyrifos is an organophosphorus (OP) insecticide that is bioactivated to chlorpyrifos-oxon, and manifests its neurotoxicity by inhibiting acetylcholinesterase (AChE). The objective of this study was to evaluate the impact of repeated nicotine exposure on the pharmacokinetics of chlorpyrifos (CPF) and its major metabolite, 3,5,6-trichloro-2-pyridinol (TCPy) in blood and urine and also to determine the impact on cholinesterase (ChE) activity in plasma and brain. Animals were exposed to 7-daily doses of either 1mg nicotine/kg or saline, and to either a single oral dose of 35mg CPF/kg or a repeated dose of 5mg CPF/kg/day for 7 days. Groups of rats were then sacrificed at multiple time-points after receiving the last dose of CPF. Repeated nicotine and CPF exposures resulted in enhanced metabolism of CPF to TCPy, as evidenced by increases in the measured TCPy peak concentration and AUC in blood. However, there was no significant difference in the amount of TCPy (free or total) excreted in the urine within the first 24-h post last dose. The extent of brain acetylcholinesterase (AChE) inhibition was reduced due to nicotine co-exposure consistent with an increase in CYP450-mediated dearylation (detoxification) versus desulfuration. It was of interest to note that the impact of nicotine co-exposure was experimentally observed only after repeated CPF doses. A physiologically based pharmacokinetic model for CPF was used to simulate the effect of increasing the dearylation V(max) based upon previously conducted in vitro metabolism studies. Predicted CPF-oxon concentrations in blood and brain were lower following the expected V(max) increase in nicotine treated groups. These model results were consistent with the experimental data. The current study demonstrated that repeated nicotine exposure could alter CPF metabolism in vivo, resulting in altered brain AChE inhibition.
常规使用烟草制品可能会改变生理和代谢功能，包括药物代谢酶，这可能会影响环境污染物的药代动力学。毒死蜱是一种有机磷（OP）杀虫剂，它会被生物转化为毒死蜱氧，通过抑制乙酰胆碱酯酶（AChE）表现出其神经毒性。本研究的目的是评估重复尼古丁暴露对血液和尿液中毒死蜱（CPF）及其主要代谢物 3,5,6-三氯-2-吡啶醇（TCPy）的药代动力学的影响，以及对血浆和大脑中胆碱酯酶（ChE）活性的影响。动物接受 7 天的 1mg/kg 尼古丁或生理盐水暴露，或单次口服 35mg/kg CPF 或连续 7 天每天 5mg/kg CPF 暴露。然后，在接受最后一剂 CPF 后的多个时间点处死各组大鼠。重复尼古丁和 CPF 暴露导致 CPF 向 TCPy 的代谢增强，这表现在血液中 TCPy 峰浓度和 AUC 的增加。然而，在最后一次剂量后 24 小时内，尿液中 TCPy（游离或总）的排泄量没有显著差异。由于尼古丁共暴露，大脑乙酰胆碱酯酶（AChE）的抑制程度降低，这与 CYP450 介导的去甲酰化（解毒）而不是脱硫作用的增加一致。值得注意的是，只有在重复 CPF 剂量后，才在实验中观察到尼古丁共暴露的影响。使用 CPF 的基于生理学的药代动力学模型来模拟基于先前进行的体外代谢研究增加去甲酰化 Vmax 的影响。在尼古丁处理组中，预期 Vmax 增加后，血液和大脑中的 CPF-氧浓度降低。这些模型结果与实验数据一致。本研究表明，重复尼古丁暴露会改变体内 CPF 的代谢，导致大脑 AChE 抑制的改变。
