West James D, Ji Chuan, Duncan Stephen T, Amarnath Venkataraman, Schneider Claus, Rizzo Carmelo J, Brash Alan R, Marnett Lawrence J
Department of Biochemistry, Vanderbilt Institute of Chemical Biology, Center in Molecular Toxicology, Vanderbilt University, Nashville, Tennessee 37232-0146, USA.
Chem Res Toxicol. 2004 Apr;17(4):453-62. doi: 10.1021/tx034248o.
The oxidation of polyunsaturated fatty acids during oxidative stress gives rise to a series of toxic alpha,beta-unsaturated aldehydes, including the electrophile 4-hydroxy-2-nonenal (4-HNE) and the related aldehydes, 4-hydroperoxy-2-nonenal (4-HPNE) and 4-oxo-2-nonenal (4-ONE). We synthesized these compounds, as well as the resolved enantiomers of 4-HNE, and compared their toxicities and apoptotic responses in the human colorectal cancer cell line RKO. All of these molecules execute similar death responses at comparable doses over almost identical time frames in RKO cells. The apoptotic response induced by 4-HPNE, 4-ONE, and 4-HNE enantiomers involves activation of caspases, proteolysis of downstream caspase targets, and nucleosomal DNA fragmentation. The results presented herein suggest that these molecules commonly activate certain signaling pathways that control cell death irrespective of their reactive properties.
在氧化应激期间，多不饱和脂肪酸的氧化会产生一系列有毒的α,β-不饱和醛，包括亲电试剂4-羟基-2-壬烯醛（4-HNE）以及相关醛类4-氢过氧-2-壬烯醛（4-HPNE）和4-氧代-2-壬烯醛（4-ONE）。我们合成了这些化合物以及4-HNE的拆分对映体，并比较了它们在人结肠癌细胞系RKO中的毒性和凋亡反应。在RKO细胞中，所有这些分子在相当的剂量下、几乎相同的时间范围内引发相似的死亡反应。4-HPNE、4-ONE和4-HNE对映体诱导的凋亡反应涉及半胱天冬酶的激活、下游半胱天冬酶靶标的蛋白水解以及核小体DNA片段化。本文给出的结果表明，这些分子通常会激活某些控制细胞死亡的信号通路，而与它们的反应特性无关。
