谷胱甘肽水平调节人红白血病细胞中HNE诱导的基因毒性。
Glutathione level regulates HNE-induced genotoxicity in human erythroleukemia cells.
作者信息
Yadav Umesh C S, Ramana Kota V, Awasthi Yogesh C, Srivastava Satish K
机构信息
Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas 77555-0647, USA.
出版信息
Toxicol Appl Pharmacol. 2008 Mar 1;227(2):257-64. doi: 10.1016/j.taap.2007.10.025. Epub 2007 Nov 17.
4-hydroxy-trans-2-nonenal (HNE) is one of the most abundant and toxic lipid aldehydes formed during lipid peroxidation by reactive oxygen species. We have investigated the genotoxic effects of HNE and its regulation by cellular glutathione (GSH) levels in human erythroleukemia (K562) cells. Incubation of K562 cells with HNE (5-10 microM) significantly elicited a 3- to 5-fold increased DNA damage in a time- and dose-dependent manner as measured by comet assay. Depletion of GSH in cells by L-buthionine-[S,R]-sulfoximine (BSO) significantly increased HNE-induced DNA damage, whereas supplementation of GSH by incubating the cells with GSH-ethyl ester significantly decreased HNE-induced genotoxicity. Further, overexpression of mGSTA4-4, a HNE-detoxifying GST isozyme, significantly prevented HNE-induced DNA damage in cells, and ablation of GSTA4-4 and aldose reductase with respective siRNAs further augmented HNE-induced DNA damage. These results suggest that the genotoxicity of HNE is highly dependent on cellular GSH/GST/AR levels and favorable modulation of the aldehyde detoxification system may help in controlling the oxidative stress-induced complications.
4-羟基反式-2-壬烯醛（HNE）是活性氧在脂质过氧化过程中形成的最丰富且毒性最强的脂质醛之一。我们研究了HNE的遗传毒性作用及其在人红白血病（K562）细胞中受细胞内谷胱甘肽（GSH）水平的调控情况。用HNE（5 - 10微摩尔）孵育K562细胞，通过彗星试验检测发现，DNA损伤以时间和剂量依赖性方式显著增加了3至5倍。用L-丁硫氨酸-[S，R]-亚砜亚胺（BSO）耗尽细胞内的GSH，显著增加了HNE诱导的DNA损伤，而用谷胱甘肽乙酯孵育细胞补充GSH则显著降低了HNE诱导的遗传毒性。此外，HNE解毒性谷胱甘肽S-转移酶同工酶mGSTA4-4的过表达显著预防了细胞中HNE诱导的DNA损伤，用各自的小干扰RNA（siRNA）敲除GSTA4-4和醛糖还原酶进一步增强了HNE诱导的DNA损伤。这些结果表明，HNE的遗传毒性高度依赖于细胞内GSH/GST/AR水平，对醛解毒系统的有利调节可能有助于控制氧化应激诱导的并发症。
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