Impact of repeated nicotine and alcohol coexposure on in vitro and in vivo chlorpyrifos dosimetry and cholinesterase inhibition.
Impact of repeated nicotine and alcohol coexposure on in vitro and in vivo chlorpyrifos dosimetry and cholinesterase inhibition.
复制标题
反复尼古丁和酒精共暴露对体外和体内毒死蜱剂量测定和胆碱酯酶抑制的影响。
DOI：
10.1080/15287394.2011.567958
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发表时间：
2011
期刊：
影响因子：
--
通讯作者：
Timchalk,C
中科院分区：
文献类型：
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作者：
Lee,S;Poet,TS;Smith,JN;Hjerpe,AL;Gunawan,R;Timchalk,C
毒死蜱（CPF）是一种有机磷杀虫剂，其代谢产物毒死蜱-氧磷（chlorpyrifos-oxon）对乙酰胆碱酯酶（AChE）的抑制作用导致其神经毒性。酒精和烟草的常规消费改变了影响其他外源性物质（包括农药）的代谢和药代动力学的代谢和生理过程。本研究评价了重复乙醇和尼古丁共暴露对体内CPF剂量测定和胆碱酯酶（ChE）反应（ChE-包括AChE和/或丁酰胆碱酯酶（BuChE））的影响。从未处理、仅乙醇（1 g/kg/d，7 d，po）和乙醇+尼古丁（1 mg/kg/d，7 d，sc）处理的大鼠组制备肝微粒体，并评价CPF的体外代谢。对于体内研究，除了CPF（1或5 mg/kg/d，po）外，还用盐水或乙醇（1 g/kg/d，po）+尼古丁（1 mg/kg/d，sc）处理大鼠7天。测定了大鼠血、尿中CPF的主要代谢产物3，5，6-三氯-2-吡啶酚（TCPy）及血浆胆碱酯酶（ChE）和脑乙酰胆碱酯酶（AChE）活性。药代动力学存在差异，与仅CPF相比，乙醇+尼古丁组的TCPy峰浓度更高，血液TCPy AUC增加（1和5 mg CPF剂量分别约为1.8和3.8倍）。与仅CPF相比，乙醇+尼古丁处理后的脑AChE活性在重复5 mg CPF/kg给药后显示出显著更少的抑制（在最后一次CPF给药后4 h分别为未处理组的96 ± 13和66 ± 7%）。尽管1-mg CPF/kg/d组的脑AChE活性受到最小程度的抑制，但乙醇+尼古丁预处理导致类似的趋势（即，略低的抑制）。由于酒精+尼古丁治疗，血浆胆碱酯酶活性没有观察到显着差异。在体外，CPF的代谢没有显着影响反复乙醇或乙醇+尼古丁暴露。与先前尼古丁和CPF暴露的研究相比，乙醇联合暴露没有明显的额外加重作用。
Chlorpyrifos (CPF) is an organophosphorus insecticide, and neurotoxicity results from inhibition of acetylcholinesterase (AChE) by its metabolite, chlorpyrifos-oxon. Routine consumption of alcohol and tobacco modifies metabolic and physiological processes impacting the metabolism and pharmacokinetics of other xenobiotics, including pesticides. This study evaluated the influence of repeated ethanol and nicotine coexposure on in vivo CPF dosimetry and cholinesterase (ChE) response (ChE- includes AChE and/or butyrylcholinesterase (BuChE)). Hepatic microsomes were prepared from groups of naive, ethanol-only (1 g/kg/d, 7 d, po), and ethanol + nicotine (1 mg/kg/d 7 d, sc)-treated rats, and the in vitro metabolism of CPF was evaluated. For in vivo studies, rats were treated with saline or ethanol (1 g/kg/d, po) + nicotine (1 mg/kg/d, sc) in addition to CPF (1 or 5 mg/kg/d, po) for 7 d. The major CPF metabolite, 3,5,6-trichloro-2-pyridinol (TCPy), in blood and urine and the plasma ChE and brain acetylcholinesterase (AChE) activities were measured in rats. There were differences in pharmacokinetics, with higher TCPy peak concentrations and increased blood TCPy AUC in ethanol + nicotine groups compared to CPF only (approximately 1.8- and 3.8-fold at 1 and 5 mg CPF doses, respectively). Brain AChE activities after ethanol + nicotine treatments showed significantly less inhibition following repeated 5 mg CPF/kg dosing compared to CPF only (96 ± 13 and 66 ± 7% of naive at 4 h post last CPF dosing, respectively). Although brain AChE activity was minimal inhibited for the 1-mg CPF/kg/d groups, the ethanol + nicotine pretreatment resulted in a similar trend (i.e., slightly less inhibition). No marked differences were observed in plasma ChE activities due to the alcohol + nicotine treatments. In vitro, CPF metabolism was not markedly affected by repeated ethanol or both ethanol + nicotine exposures. Compared with a previous study of nicotine and CPF exposure, there were no apparent additional exacerbating effects due to ethanol coexposure.