Costa L G, Murphy S D
Res Commun Chem Pathol Pharmacol. 1984 Jun;44(3):389-400.
This study was undertaken to investigate whether depletion of hepatic nonprotein sulfhydryls (NPSH) by acetaminophen would potentiate the toxicity of organophosphates which are detoxified by glutathione transferases. Acetaminophen caused a dose dependent decrease of NPSH in mouse liver. At the dose of 600 mg/kg, which decreased hepatic NPSH by 90%, acetaminophen did not potentiate the effects of the organophosphorus insecticides methylchlorpyrifos, methylparathion or dichlorovos on esterases. On the other hand, depletion of hepatic NPSH by diethylmaleate increased the toxicities of the insecticides. While the reported inhibition of mixed function oxidase activity by acetaminophen may explain the lack of potentiation of methylchlorpyrifos and methylparathion which need to be converted to their oxygen analogs, its failure in potentiating the toxicity of dichlorvos, which does not require metabolic activation, suggests that other mechanisms are involved. The finding that acetaminophen decreased NPSH only in the liver and, to a minor extent, in the kidney, while diethylmaleate caused significant depletion of NPSH in several tissues, suggests that extrahepatic glutathione may be relevant to the detoxication of certain organophosphates.
本研究旨在调查对乙酰氨基酚导致肝脏非蛋白质巯基（NPSH）耗竭是否会增强经谷胱甘肽转移酶解毒的有机磷酸酯的毒性。对乙酰氨基酚导致小鼠肝脏中NPSH呈剂量依赖性降低。在600 mg/kg的剂量下，肝脏NPSH降低了90%，对乙酰氨基酚并未增强有机磷杀虫剂甲基毒死蜱、甲基对硫磷或敌敌畏对酯酶的作用。另一方面，马来酸二乙酯导致肝脏NPSH耗竭增加了这些杀虫剂的毒性。虽然据报道对乙酰氨基酚抑制混合功能氧化酶活性可能解释了对毒死蜱和甲基对硫磷缺乏增强作用，因为它们需要转化为其氧类似物，但它未能增强敌敌畏的毒性，敌敌畏不需要代谢活化，这表明涉及其他机制。对乙酰氨基酚仅在肝脏中降低NPSH，在肾脏中降低程度较小，而马来酸二乙酯在多个组织中导致NPSH显著耗竭，这一发现表明肝外谷胱甘肽可能与某些有机磷酸酯的解毒有关。
