Age-related differences in parathion and chlorpyrifos toxicity in male rats: Target and nontarget esterase sensitivity and cytochrome P450-mediated metabolism
Age-related differences in parathion and chlorpyrifos toxicity in male rats: Target and nontarget esterase sensitivity and cytochrome P450-mediated metabolism
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DOI：
10.1006/taap.1997.8303
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发表时间：
1997-12-01
影响因子：
3.8
通讯作者：
Chambers, JE
中科院分区：
文献类型：
--
作者：
Atterberry, TT;Burnett, WT;Chambers, JE
幼年大鼠比成年大鼠更容易受到硫代磷酸酯杀虫剂敌百虫和毒死蜱的急性毒性的影响。在雄性Sprague-Dawley大鼠中研究了脑乙酰胆碱酯酶和肝脂肪酯酶（羧酸酯酶）、细胞色素P450以及P450介导的这两种硫代磷酸酯杀虫剂代谢的发育变化。大脑皮质（但不包括延脑）中乙酰胆碱酯酶和肝脏脂肪酶的比活性随着年龄的增长而增加，这表明与幼年动物相比，成年动物中分别存在更多的目标酯酶和更多的保护性酯酶。脑乙酰胆碱酯酶抑制对氧磷和毒死蜱的敏感性，测定的IC 50值，没有随年龄的变化显着，而肝脂肪酯酶抑制的敏感性随年龄的增长而下降。在新生儿和成人肝微粒体之间观察到P450介导的活化（脱硫）（6- 14倍）和解毒（脱芳基）（2- 4倍）以及P450（7倍）和蛋白质（2倍）浓度的逐渐增加。微粒体pentoxyresorufin O-脱烷基酶活性遵循类似于脱硫和脱芳基的发育模式，在新生儿和成人之间显示出16倍的增加。然而，微粒体乙氧基试卤灵O-脱乙基酶活性增加，直到21日龄，显示16倍的增加，然后在成年期下降到10倍的水平高于新生儿。这些结果表明，目标酶的敏感性是不负责与年龄相关的毒性差异，也不是潜在的肝生物活化，而较低水平的肝脂肪酶介导的保护和P450介导的脱芳基化可能有助于显着更大的敏感性青少年硫代磷酸酯毒性。(C)北京：科学出版社.
Juvenile rats are more susceptible to the acute toxicity of the phosphorothionate insecticides parathion and chlorpyrifos than are adult rats. Developmental changes in brain acetylcholinesterase and hepatic aliesterase (carboxylesterase), cytochrome P450, and the P450-mediated metabolism of these two phosphorothionate insecticides were investigated in male Sprague-Dawley rats. Specific activities of acetylcholinesterase in cerebral cortex, but not medulla oblongata, and of liver aliesterases increased with age, indicating the presence of both more target esterases and more protective esterases, respectively, in the adult compared to the juvenile animal. Sensitivity of the brain acetylcholinesterase to inhibition by paraoxon and chlorpyrifosoxon, as measured by IC50 values, did not change significantly with age, whereas the hepatic aliesterase sensitivity to inhibition decreased with age. Progressive increases in activities of P450-mediated activation (desulfuration) (6- to 14-fold) and detoxication (dearylation) (2- to 4-fold), as well as concentrations of P450 (7-fold) and protein (2-fold), were observed between neonate and adult hepatic microsomes. Microsomal pentoxyresorufin O-dealkylase activity followed a developmental pattern similar to desulfuration and dearylation, displaying a 16-fold increase between neonates and adults. However, microsomal ethoxyresorufin O-deethylase activity increased until 21 days of age, displaying a 16-fold increase, then decreased in adulthood to a level 10-fold higher than neonates. These results indicate that target enzyme sensitivity is not responsible for age-related toxicity differences, nor is the potential for hepatic bioactivation, whereas lower levels of hepatic aliesterase-mediated protection and P450-mediated dearylation probably contribute significantly to the greater sensitivity of juveniles to phosphorothionate toxicity. (C) 1997 Academic Press.