O'Shaughnessy J A, Sultatos L G
Department of Pharmacology and Toxicology, University of Medicine and Dentistry of New Jersey, Newark 07103-2714, USA.
Biochem Pharmacol. 1995 Nov 27;50(11):1925-32. doi: 10.1016/0006-2952(95)02089-6.
Phosphorothioate insecticides such as parathion (O,O-diethyl-O-p-nitrophenyl phosphorothioate) undergo P450-dependent oxidative desulfuration, leading to both activation and detoxification of these compounds. Consequently, alterations in P450-dependent oxidative desulfuration may affect the acute toxicities of these insecticides. In the present study, pretreatment of mice with 15% ethanol in the drinking water for 6 days antagonized the acute toxicity of parathion, but not its toxic metabolite paraoxon (O,O-diethyl-O-p-nitrophenyl phosphate), suggesting that ethanol affected the oxidative desulfuration of this insecticide. The presence of ethanol within hepatic microsomal incubations did not alter the P450-dependent formation of paraoxon (activation) and p-nitrophenol (detoxification), although p-nitrophenol levels were increased in the presence of ethanol as a result of inhibition of its biotransformation to 4-nitrocatechol by CYP2E1. Ethanol exposure reduced hepatic pyruvate levels, but had no effect on levels of lactate, isocitrate, alpha-ketoglutarate, and malate. Calculation of cytosolic NAD+/NADH and cytosolic NADP+/NADPH redox ratios did not reveal any detectable difference in redox state between control and ethanol-treated mice. Since ethanol did not alter directly the P450-dependent activation or detoxification of parathion, and did not decrease NADPH levels, ethanol's antagonism of the acute toxicity of parathion may result from reduced availability of O2.
硫代磷酸酯类杀虫剂，如对硫磷（O,O - 二乙基 - O - 对硝基苯基硫代磷酸酯），会经历细胞色素P450依赖的氧化脱硫反应，导致这些化合物的活化和解毒。因此，细胞色素P450依赖的氧化脱硫反应的改变可能会影响这些杀虫剂的急性毒性。在本研究中，给小鼠饮用含15%乙醇的水预处理6天，可拮抗对硫磷的急性毒性，但对其有毒代谢产物对氧磷（O,O - 二乙基 - O - 对硝基苯基磷酸酯）无效，这表明乙醇影响了这种杀虫剂的氧化脱硫反应。肝微粒体孵育体系中存在乙醇时，细胞色素P450依赖的对氧磷（活化）和对硝基苯酚（解毒）的形成并未改变，尽管由于细胞色素P450 2E1对其向4 - 硝基邻苯二酚生物转化的抑制作用，乙醇存在时对硝基苯酚水平有所升高。乙醇暴露降低了肝脏丙酮酸水平，但对乳酸、异柠檬酸、α - 酮戊二酸和苹果酸水平没有影响。计算胞质NAD⁺/NADH和胞质NADP⁺/NADPH氧化还原比值，未发现对照小鼠和乙醇处理小鼠之间氧化还原状态有任何可检测到的差异。由于乙醇并未直接改变细胞色素P450依赖的对硫磷的活化或解毒，也未降低NADPH水平，乙醇对硫磷急性毒性的拮抗作用可能是由于氧气供应减少所致。
