Gene therapy to prevent organophosphate intoxication
Gene therapy to prevent organophosphate intoxication
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DOI：
10.1006/taap.2001.9169
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发表时间：
2001-05-15
影响因子：
3.8
通讯作者：
Munford, RS
中科院分区：
文献类型：
--
作者：
Cowan, J;Sinton, CM;Munford, RS
PON 1对氧磷酶/芳基酯酶在肝脏和血液中的特异性水解活性提供了天然屏障，阻止有机磷毒素进入中枢和外周神经系统。PON 1酶浓度的遗传差异可能决定人类对有机磷损伤的易感性水平。为了测试是否通过基因治疗提高血清中PON 1酶的水平可能会提供更多的保护，我们比较了静脉注射含有PON 1-LQ或PON 1-LR基因或无PON 1基因的重组腺病毒后4天暴露于毒死蜱的小鼠全脑乙酰胆碱酯酶的失活程度。这两种重组病毒含有PON 1基因提高血清芳基酯酶浓度约60%，并显着防止脑乙酰胆碱酯酶的失活。这些发现表明，通过基因递送载体提高PON 1酶的血清水平，在化学物质进入大脑之前通过水解破坏提高了有机磷毒性的阈值。(C)北京：科学出版社.
The specific hydrolytic activity of PON1 paraoxonase/arylesterase enzymes in liver and blood provides a natural barrier against the entry of organophosphate toxins into the central and peripheral nervous systems. Inherited differences in PON1 enzyme concentrations may determine levels of susceptibility to organophosphate injury in humans. To test whether boosting serum levels of PON1 enzymes by gene therapy might provide increased protection, we compared the degree of inactivation of whole brain acetylcholinesterase of mice exposed to chlorpyrifos 4 days after intravenous injection of recombinant adenoviruses containing PON1-LQ or PON1-LR genes or no PON1 gene. Both recombinant viruses containing PON1 genes boosted serum arylesterase concentrations by approximately 60% and significantly prevented the inactivation of brain acetylcholinesterase. Some mice were completely protected, These findings indicate that boosting serum levels of PON1 enzymes by a gene delivery vector raises the threshold for organophosphate toxicity by hydrolytic destruction before the chemical can enter the brain. (C) 2001 Academic Press.