Ascorbic acid reverses the prolonged anesthetic action of pentobarbital in Akr1a-knockoutmice
Ascorbic acid reverses the prolonged anesthetic action of pentobarbital in Akr1a-knockoutmice
复制标题
抗坏血酸逆转 Akr1a 敲除小鼠中戊巴比妥的长期麻醉作用
DOI：
10.1016/j.lfs.2013.12.004
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发表时间：
2014
期刊：
影响因子：
6.1
通讯作者：
Junichi Fujiito c,YutaMatsuoka d,
中科院分区：
文献类型：
--
作者：
Junitsu Ito a,Noriyuki Otsuki a;Xuhong Zhang a;Tasuku Konno a;Toshihiro Kurahashi a,Motoko Takahashi b;Mayumi YamaKen-ichi Yamada d;Satoshi Miyata e;Junichi Fujiito c,YutaMatsuoka d,
醛还原酶（AKR1A）是醛酮还原酶超家族的一员，在肝脏中高度表达，参与羰基化合物的解毒和抗坏血酸的生物合成。与野生型小鼠相比，Akr1a基因敲除（Akr1a−/−）小鼠和人转基因akrla基因敲除（Akr1atg/+）小鼠的麻醉作用与戊巴比比延长（Akr1a−/−）小鼠和缩短（Akr1atg/+）人转基因akrla基因敲除（Akr1atg/+）小鼠不同。主要方法研究戊巴比妥对akr1基因修饰小鼠麻醉效果的改变。野生型小鼠肝脏细胞质蛋白和纯化大鼠AKR1A均不能直接还原戊巴比妥。抗坏血酸给药可以中和akr1a−/−小鼠的翻正反射（LORR）丧失的延长时间，但在给药前将戊巴比妥与抗坏血酸预孵育并没有改变麻醉效果。这些结果表明抗坏血酸不能直接还原戊巴比妥。构成戊巴比妥有效解毒系统的一些细胞色素p450的酶活性和蛋白质水平在转基因小鼠中没有变化。因此，抗坏血酸对肝脏的解毒系统也没有影响。戊巴比妥引起的akr1a−/−小鼠LORR持续时间的延长和抗坏血酸对麻醉作用的中和以及其他结果表明，抗坏血酸改变了神经系统对麻醉剂的反应。在抗坏血酸缺乏的情况下，戊巴比妥的作用会增加，在麻醉营养不良患者时可能需要考虑到这一点。
AimsAldehyde reductase (AKR1A), a member of the aldo-keto reductase superfamily, is highly expressed in the liver and is involved in both the detoxification of carbonyl compounds and ascorbic acid biosynthesis. By comparison with wild-type mice,Akr1a-knockout (Akr1a−/−) mice and humanAkrla-transgenic (Akr1atg/+) mice experience different anesthetic actions from pentobarbital—prolonged inAkr1a-knockout (Akr1a−/−) mice and shortened in humanAkrla-transgenic (Akr1atg/+) mice.Main methodsWe investigated this alteration in the anesthetic efficacy of pentobarbital inAkr1agenetically modified mice.Key findingsNeither the cytosolic protein of wild-type mouse liver nor purified rat AKR1A directly reduced pentobarbital. Ascorbic acid administration neutralized the prolonged duration of the loss of the righting reflex (LORR) inAkr1a−/−mice, but preincubation of pentobarbital with ascorbic acid prior to administration did not change the anesthetic effect. Those results indicated that ascorbic acid does not directly reduce pentobarbital. Enzymatic activities and levels of the proteins of some cytochrome P450s that make up a potent detoxification system for pentobarbital showed no changes in the genetically modified mice examined. Thus, ascorbic acid also had no effect on the detoxification system in the liver. The prolonged duration of LORR in theAkr1a−/−mice caused by pentobarbital and the neutralization of the anesthetic effect by ascorbic acid together with other results imply that ascorbic acid alters the responses of the neuronal system to anesthetics.SignificancePentobarbital action is increased under conditions of ascorbic acid deficiency, and this may have to be taken into account when anesthetizing malnourished patients.