Catalase mediates acetaldehyde formation from ethanol in fetal and neonatal rat brain
Catalase mediates acetaldehyde formation from ethanol in fetal and neonatal rat brain
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DOI：
10.1097/00000374-199709000-00020
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发表时间：
1997-09-01
影响因子：
3.2
通讯作者：
Henderson, GI
中科院分区：
文献类型：
--
作者：
HambyMason, R;Chen, JJ;Henderson, GI
胎儿接触乙醇(E)对大脑发育的有害影响已得到充分证实，但尚不确定母亲摄入E的神经毒性是由E本身产生的，还是由其主要代谢物乙醛(Acho)产生的，还是两者兼而有之。目前的研究表明，未成熟大鼠大脑匀浆可以通过过氧化氢酶(CAT)介导的反应产生Acho，并且该系统可能在体内产生Acho。取第19天胎鼠脑匀浆，与50 mM的E孵育。当与CAT抑制剂(叠氮化钠或3-氨基三氮唑)孵育时，Acho的形成被阻止，而酒精脱氢酶抑制剂4-甲基吡唑和P-450抑制剂都不会减少Acho的产生。孕鼠口服E(4g/kg)后3h，胎脑Acho水平升高至14.28+/-1.82 nm/g组织。第19天胎儿大脑的CAT活性基线是成人的4.5倍(p<；0.05)。Western印迹分析表明，第19天胎脑中CAT蛋白的表达水平是成人脑的2.5倍。单次给药1h后，第19天胎脑CAT活性升高8.2U/mg蛋白。在5天大的新生儿大脑中，在“第三个三个月”的大脑生长突发期，基线CAT活性是成人值的两倍(p<；0.05)，体内P-day方案使Acho水平增加到对照组的四倍，同时CAT活性增加1.7倍。这可以通过给予CAT抑制剂(3-氨基-1，2，4-三氮唑)来预防。暴露于E的新生儿大脑的免疫组织化学染色显示存在乙醛-蛋白质加合物。我们的结论是，Acho可能是通过CAT介导的E氧化在大鼠胎儿和新生脑组织中产生的，这一现象可能是宫内E暴露的神经毒性效应的一个重要因素。
Fetal ethanol (E) exposure has well documented deleterious effects on brain development, yet it is uncertain if the neurotoxicity of maternal E consumption is generated by E itself, by its primary metabolite acetaldehyde (AcHO), or both. The current studies present evidence that homogenates of immature rat brains can generate AcHO via a catalase (CAT)-mediated reaction and that AcHO may be produced in vivo by this system. Homogenates of day 19 fetal rat brain were incubated with E (50 mM). When incubated with CAT inhibitors (sodium azide or 3-aminotriazole), AcHO formation was blocked, whereas neither the alcohol dehydrogenase inhibitor, 4-methylpyrazole, nor P-450 inhibitors decreased AcHO production. Three hours after one oral dose of E (4 g/kg) to a pregnant dam (gestation day 19), AcHO levels in fetal brain increased to 14.28 +/- 1.82 nM/g tissue. Baseline CAT activity in day 19 fetal brains was 4.5 times adult values (p < 0.05). Western blot analysis determined that CAT protein level in the day 19 fetal brain exceeded that in adult brain by 2.5 times. One hour after a single dose of E, CAT activity in day 19 fetal brain increased by 8.2 units/mg protein. In 5-day-old neonatal brains during the ''third trimester'' brain growth spurt, baseline CAT activity was twice the adult values (p < 0.05) and a P-day in vivo E regimen increased AcHO levels to four times the control values, with a concomitant 1.7-fold increase in CAT activity. This was prevented by administration of a CAT inhibitor (3-amino-1,2,4-triazole). Immunohistochemical staining of neonatal brains exposed to E illustrated the presence of acetaldehyde-protein adducts. We conclude that AcHO is likely produced in rat fetal and neonatal brain via CAT-mediated oxidation of E. This phenomenon may be an important factor in the neurotoxic effects of in utero E exposure.