In vitro sensitivity of cholinesterases and [3H]oxotremorine-M binding in heart and brain of adult and aging rats to organophosphorus anticholinesterases.
In vitro sensitivity of cholinesterases and [3H]oxotremorine-M binding in heart and brain of adult and aging rats to organophosphorus anticholinesterases.
复制标题
胆碱酯酶的体外敏感性以及成年和衰老大鼠心脏和大脑中[3H]氧化震颤素-M 结合对有机磷抗胆碱酯酶的敏感性。
DOI：
10.1016/j.bcp.2008.08.001
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发表时间：
2008
影响因子：
5.8
通讯作者：
Pope,CareyN
中科院分区：
文献类型：
--
作者：
Mirajkar,Nikita;Pope,CareyN
有机磷 (OP) 杀虫剂通过抑制乙酰胆碱酯酶而引起毒性，导致乙酰胆碱积累并过度刺激胆碱能受体。一些 OP 杀虫剂与其他大分子结合，包括丁酰胆碱酯酶和胆碱能受体。虽然 OP 抗胆碱酯酶的神经毒性已被广泛研究，但对心脏功能的影响却很少受到关注。我们比较了成年（3个月）和老年（18个月）大鼠皮质和心脏中的乙酰胆碱酯酶、丁酰胆碱酯酶和[3H]氧化震颤素-M与毒蕈碱受体结合对毒死蜱、甲基对硫磷及其活性代谢物毒死蜱氧磷和甲基对氧磷的体外敏感性。使用选择性抑制剂，无论年龄如何，大脑中的绝大多数胆碱酯酶被定义为乙酰胆碱酯酶，而丁酰胆碱酯酶是心脏中的主要胆碱酯酶。在心脏中，丁酰胆碱酯酶对毒死蜱的抑制作用明显比乙酰胆碱酯酶更敏感，并且衰老大鼠组织中的丁酰胆碱酯酶比成年大鼠的酶更敏感，这可能是由于A-酯酶介导的解毒作用存在差异。在大脑中也发现了相对相似的差异。相比之下，在心脏和大脑中，乙酰胆碱酯酶比丁酰胆碱酯酶对甲基对氧磷更敏感，但没有发现与年龄相关的差异。两种氧突以浓度依赖性方式取代两个年龄组心脏和大脑中的[3H]氧化震颤素-M 结合。毒死蜱没有效果，但甲基对硫磷是两个年龄组心脏和大脑中结合的有效置换剂。 OP与胆碱能大分子相互作用的这种与年龄相关的差异可能很重要，因为环境中可能暴露于杀虫剂以及在与年龄相关的神经系统疾病中使用抗胆碱酯酶。
Organophosphorus (OP) insecticides elicit toxicity via acetylcholinesterase inhibition, allowing acetylcholine accumulation and excessive stimulation of cholinergic receptors. Some OP insecticides bind to additional macromolecules including butyrylcholinesterase and cholinergic receptors. While neurotoxicity from OP anticholinesterases has been extensively studied, effects on cardiac function have received less attention. We compared the in vitro sensitivity of acetylcholinesterase, butyrylcholinesterase and [3H]oxotremorine-M binding to muscarinic receptors in the cortex and heart of adult (3 months) and aging (18 months) rats to chlorpyrifos, methyl parathion and their active metabolites chlorpyrifos oxon and methyl paraoxon. Using selective inhibitors, the great majority of cholinesterase in brain was defined as acetylcholinesterase, while butyrylcholinesterase was the major cholinesterase in heart, regardless of age. In the heart, butyrylcholinesterase was markedly more sensitive than acetylcholinesterase to inhibition by chlorpyrifos oxon, and butyrylcholinesterase in tissues from aging rats was more sensitive than enzyme from adults, possibly due to differences in A-esterase mediated detoxification. Relatively similar differences were noted in brain. In contrast, acetylcholinesterase was more sensitive than butyrylcholinesterase to methyl paraoxon in both heart and brain, but no age-related differences were noted. Both oxons displaced [3H]oxotremorine-M binding in heart and brain of both age groups in a concentration-dependent manner. Chlorpyrifos had no effect but methyl parathion was a potent displacer of binding in heart and brain of both age groups. Such OP and age-related differences in interactions with cholinergic macromolecules may be important because of potential for environmental exposures to insecticides as well as the use of anticholinesterases in age-related neurological disorders.