Xie C, Lovell M A, Markesbery W R
Sanders-Brown Center on Aging, University of Kentucky, Lexington 40536-0230, USA.
Free Radic Biol Med. 1998 Nov 15;25(8):979-88. doi: 10.1016/s0891-5849(98)00186-5.
Peroxidation of polyunsaturated fatty acids (PUFA), particularly arachidonic acid, leads to the generation of reactive aldehydes, including 4-hydroxynonenal (HNE). Recent studies have demonstrated an increase in lipid peroxidation, a decline in PUFA, as well as an increase in HNE, and a decrease in glutathione transferase (GST) in the brain in Alzheimer's disease. Four-hydroxynonenal is toxic to cultured neurons and to the brain of experimental animals. Although glutathione (GSH) has been shown to offer protection against HNE, no enzymatic system has been described which serves to detoxify these reactive species in neuronal cultures. Here, we describe the use of GST in the protection of neuronal cultures against HNE toxicity. Glutathione transferases are a superfamily of enzymes functioning to catalyze the nucleophilic attack of GSH on electrophilic groups on a second substrate. These enzymes function efficiently with 4-hydroxyalkenals, particularly HNE, as substrates. To investigate the protective effects of GST against HNE, primary hippocampal cultures were pretreated with GST before exposure to toxic doses of HNE which led to a statistically significant enhancement in cell survival. Pretreatment of cultures with equivalent levels of heat inactivated GST or antibody against GST did not offer protection against HNE. Control cultures pretreated with GST also demonstrated enhanced survival compared with control cells receiving no pretreatment. These data suggest that GST may be an important source of protection against the toxic effects of HNE.
多不饱和脂肪酸（PUFA），尤其是花生四烯酸的过氧化作用会导致包括4-羟基壬烯醛（HNE）在内的反应性醛类物质的生成。最近的研究表明，在阿尔茨海默病患者的大脑中，脂质过氧化作用增强、PUFA含量下降、HNE含量增加以及谷胱甘肽转移酶（GST）含量降低。4-羟基壬烯醛对培养的神经元和实验动物的大脑具有毒性。尽管已证明谷胱甘肽（GSH）可提供针对HNE的保护作用，但尚未描述在神经元培养物中用于解毒这些反应性物质的酶系统。在此，我们描述了使用GST保护神经元培养物免受HNE毒性的作用。谷胱甘肽转移酶是一类酶的超家族，其功能是催化GSH对第二种底物上亲电基团的亲核攻击。这些酶以4-羟基烯醛，特别是HNE作为底物时能高效发挥作用。为了研究GST对HNE的保护作用，在暴露于有毒剂量的HNE之前，先用GST对原代海马培养物进行预处理，这导致细胞存活率有统计学意义的提高。用同等水平的热灭活GST或抗GST抗体对培养物进行预处理并不能提供针对HNE的保护作用。与未进行预处理的对照细胞相比，用GST预处理的对照培养物也显示出存活率提高。这些数据表明，GST可能是抵御HNE毒性作用的重要保护来源。
