Zheng Ruijin, Dragomir Ana-Cristina, Mishin Vladimir, Richardson Jason R, Heck Diane E, Laskin Debra L, Laskin Jeffrey D
Pharmacology and Toxicology, Rutgers University-Ernest Mario School of Pharmacy, Piscataway, NJ, USA.
Environmental & Occupational Medicine, Rutgers University-Robert Wood Johnson Medical School, Piscataway, NJ, USA.
Toxicol Appl Pharmacol. 2014 Aug 15;279(1):43-52. doi: 10.1016/j.taap.2014.04.026. Epub 2014 May 14.
The lipid peroxidation end-product 4-hydroxynonenal (4-HNE) is generated in tissues during oxidative stress. As a reactive aldehyde, it forms Michael adducts with nucleophiles, a process that disrupts cellular functioning. Liver, lung and brain are highly sensitive to xenobiotic-induced oxidative stress and readily generate 4-HNE. In the present studies, we compared 4-HNE metabolism in these tissues, a process that protects against tissue injury. 4-HNE was degraded slowly in total homogenates and S9 fractions of mouse liver, lung and brain. In liver, but not lung or brain, NAD(P)+ and NAD(P)H markedly stimulated 4-HNE metabolism. Similar results were observed in rat S9 fractions from these tissues. In liver, lung and brain S9 fractions, 4-HNE formed protein adducts. When NADH was used to stimulate 4-HNE metabolism, the formation of protein adducts was suppressed in liver, but not lung or brain. In both mouse and rat tissues, 4-HNE was also metabolized by glutathione S-transferases. The greatest activity was noted in livers of mice and in lungs of rats; relatively low glutathione S-transferase activity was detected in brain. In mouse hepatocytes, 4-HNE was rapidly taken up and metabolized. Simultaneously, 4-HNE-protein adducts were formed, suggesting that 4-HNE metabolism in intact cells does not prevent protein modifications. These data demonstrate that, in contrast to liver, lung and brain have a limited capacity to metabolize 4-HNE. The persistence of 4-HNE in these tissues may increase the likelihood of tissue injury during oxidative stress.
脂质过氧化终产物4-羟基壬烯醛（4-HNE）在氧化应激期间于组织中生成。作为一种反应性醛类，它与亲核试剂形成迈克尔加成物，这一过程会破坏细胞功能。肝脏、肺和脑对异源物诱导的氧化应激高度敏感，并易于生成4-HNE。在本研究中，我们比较了这些组织中4-HNE的代谢情况，该过程可防止组织损伤。4-HNE在小鼠肝脏、肺和脑的全匀浆及S9组分中降解缓慢。在肝脏中，而非肺或脑中，NAD(P)+和NAD(P)H显著刺激4-HNE代谢。在来自这些组织的大鼠S9组分中也观察到了类似结果。在肝脏、肺和脑的S9组分中，4-HNE形成了蛋白质加合物。当使用NADH刺激4-HNE代谢时，肝脏中蛋白质加合物的形成受到抑制，但肺和脑中未受抑制。在小鼠和大鼠组织中，4-HNE也可被谷胱甘肽S-转移酶代谢。在小鼠肝脏和大鼠肺中观察到最高活性；在脑中检测到相对较低的谷胱甘肽S-转移酶活性。在小鼠肝细胞中，4-HNE被迅速摄取并代谢。同时，形成了4-HNE-蛋白质加合物，这表明完整细胞中的4-HNE代谢并不能防止蛋白质修饰。这些数据表明，与肝脏相比，肺和脑代谢4-HNE的能力有限。4-HNE在这些组织中的持续存在可能会增加氧化应激期间组织损伤的可能性。
