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首页> 外文期刊>Life sciences >Oxidative mechanisms for the biotransformation of 1-methyl-1,6-dihydropyridine-2-carbaldoxime to pralidoxime chloride.
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Oxidative mechanisms for the biotransformation of 1-methyl-1,6-dihydropyridine-2-carbaldoxime to pralidoxime chloride.

机译：将1-甲基-1,6-二氢吡啶-2-氯甲酰胺的生物转化的氧化机制为pro硫代硫肟。

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AIMS: Due to pralidoxime chloride's (2-PAM) positive charge, it's penetration through the blood brain barrier (BBB) and reactivation of organophosphate (OP) inhibited central nervous system (CNS) acetylcholinesterase (AChE) is poor. The results of CNS inhibited AChE are seizures. Pro-2-PAM (1-methyl-1,6-dihydropyridine-2-carbaldoxime), a pro-drug of 2-PAM, due to higher hydrophobicity, penetrates the BBB better but must be oxidized to 2-PAM, the active form of the oxime to reactivate CNS AChE in order to abrogate seizures. In this study, we characterize the in vivo mechanism of pro-2-PAM oxidation. MAIN METHODS: A high pressure liquid chromatography (HPLC) assay was developed to quantify the conversion of pro-2-PAM to 2-PAM. NADPH oxidase activity was measured by a photo-luminescence assay using lucigenin substrate. Upon analysis, the rate of NADPH induced oxidation suggested that an alternate mechanism may be involved. Therefore, various enzyme co-factors of oxidation-reduction enzyme systems were evaluated, including nicotinamide adenine dinucleotide (NAD), nicotinamide adenine dinucleotide phosphate (NADP), flavin adenine dinucleotide (FAD), riboflavin 5'-phosphate (FMN), and riboflavin. Next, a spectrophotometric assay was developed to measure the conversion of pro-2-PAM to 2-PAM in the presence of riboflavin. KEY FINDINGS: In guinea pig brain homogenate, diphenyleneiodonium (DPI), a specific NADPH oxidase inhibitor, reduced pro-2-PAM to 2-PAM conversion to less than 25%. In contrast, riboflavin, FAD, and FMN rapidly oxidized all pro-2-PAM to 2-PAM in an in vitro assay. Riboflavin oxidized pro-2-PAM reactivated diisopropylfluorophosphate (DFP) inhibited AChE. SIGNIFICANCE: The present study shows that pro-2-PAM was rapidly oxidized by riboflavin to 2-PAM, which reactivated organophosphate (OP)-inhibited AChE.
机译：目的：由于氯化石氯化物（2-PAM）正电荷，它通过血脑屏障（BBB）渗透，有机磷酸盐（OP）的再活化抑制中枢神经系统（CNS）乙酰胆碱酯酶（ACHE）差。 CNS抑制疼痛的结果是癫痫发作。 PRO-2-PAM（1-甲基-1,6-二氢吡啶-2-马巴甲氧化肟），一种疏水性较高，渗透渗透性，但必须氧化成2-PAM，活跃肟的形式重新激活CNS疼痛以消除癫痫发作。在这项研究中，我们表征了Pro-2-PAM氧化的体内机制。主要方法：开发了高压液相色谱（HPLC）测定以量化Pro-2-PAM至2-PAM的转化。使用含叶蛋白基质的光发光测定法测量NADPH氧化酶活性。在分析后，NADPH诱导氧化的速率表明可以涉及交替机制。因此，评估氧化还原酶系统的各种酶协同因素，包括烟酰胺腺嘌呤二核苷酸（NAD），烟酰胺腺嘌呤二核苷酸磷酸（NADP），黄蛋白腺嘌呤二核苷酸（FAD），核黄素5'-磷酸酯（FMN）和核黄素。接下来，开发分光光度法测定以测量核黄素存在下PRO-2-PAM至2-PAM的转化。主要发现：在豚鼠脑匀浆中，二苯基碘鎓（DPI），特定的NADPH氧化酶抑制剂，将PRO-2-PAM转化为2-PAM转化率小于25％。相反，核黄素，FAD和FMN在体外测定中快速氧化所有PRO-2-PAM至2-PAM。 Riboflavin氧化Pro-2-PAM再激活二异丙基氟磷酸磷酸（DFP）抑制疼痛。意义：本研究表明，通过Riboflavin至2-PAM迅速氧化Pro-2-PAM，其重新激活有机磷酸酯（OP） - 抑制疼痛。

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