Misra P, Srivastava S K, Singhal S S, Awasthi S, Awasthi Y C, Boor P J
Department of Pathology, University of Texas Medical Branch, Galveston 77555, USA.
Toxicol Appl Pharmacol. 1995 Jul;133(1):27-33. doi: 10.1006/taap.1995.1123.
Allylamine (AA) is an electrophilic amine with a long history of experimental usage because of its extremely potent and relatively specific cardiovascular toxicity; it has been utilized in a variety of experimental models attempting to mimic human atherosclerotic lesions, myocardial infarction, and vascular injury. Even though the exact mechanisms by which AA causes vascular lesions remain unresolved, recent studies on the acute effects of AA exposure in rats strongly suggest that deamination to the aldehyde acrolein, oxidative stress, and the resultant increase in lipid peroxidation, generation of .OH radicals, and acute depletion of glutathione (GSH) may be some of the causative factors in AA-induced vascular lesions. Since glutathione S-transferase 8-8 (GST8-8) of rat belongs to a distinct subgroup of GST isozymes involved in the detoxification of products of lipid peroxidation, we designed studies to examine the effects of AA exposure on this GST isoform in rat aorta using Western blotting and immunohistochemical techniques. The results of these studies demonstrate that GST8-8 is expressed in rat aorta and is dramatically induced upon AA exposure. By immunohistochemistry, GST8-8 was localized in the smooth muscle cells of the vascular media which is believed to be the site of metabolism of AA. A significant increase in gamma-glutamylcysteine synthetase activity and GST activity toward 4-hydroxynonenal and acrolein, which are preferred substrates of GST8-8, was seen as early as 3 days following AA treatment. Alterations in GSH and other GSH-related enzymes at 3 and 10 days support the concept that--upon AA exposure--aortic defense mechanisms respond early and induction of GSH biosynthesis and rat GST8-8 occur to alleviate the toxic effects of acrolein, a major, genotoxic product of AA metabolism. The presence of GST8-8 in the vasculature, which is constantly exposed to products of lipid peroxidation, and its induction by AA, suggest that GST8-8 plays a key role in protecting blood vessels against oxidative stress and hence, may be involved in the atherogenic process.
烯丙胺（AA）是一种亲电子胺，因其具有极强且相对特异的心血管毒性，有着悠久的实验应用历史；它已被用于多种试图模拟人类动脉粥样硬化病变、心肌梗死和血管损伤的实验模型中。尽管AA导致血管病变的确切机制尚未明确，但近期关于大鼠暴露于AA的急性效应的研究强烈表明，AA脱氨生成醛丙烯醛、氧化应激以及由此导致的脂质过氧化增加、·OH自由基生成和谷胱甘肽（GSH）急性耗竭可能是AA诱导血管病变的一些致病因素。由于大鼠的谷胱甘肽S-转移酶8-8（GST8-8）属于参与脂质过氧化产物解毒的GST同工酶的一个独特亚组，我们设计了研究，使用蛋白质免疫印迹法和免疫组织化学技术来检测AA暴露对大鼠主动脉中这种GST同工型的影响。这些研究结果表明，GST8-8在大鼠主动脉中表达，且在AA暴露后显著诱导。通过免疫组织化学方法，GST8-8定位于血管中层的平滑肌细胞，而血管中层被认为是AA代谢的部位。早在AA处理后3天，就观察到γ-谷氨酰半胱氨酸合成酶活性以及GST对4-羟基壬烯醛和丙烯醛（GST8-8的优选底物）的活性显著增加。在3天和10天时GSH及其他与GSH相关的酶的变化支持了这样的概念，即AA暴露后，主动脉防御机制会早期响应，GSH生物合成和大鼠GST8-8的诱导会发生，以减轻丙烯醛（AA代谢的一种主要的基因毒性产物）的毒性作用。GST8-8存在于不断暴露于脂质过氧化产物的脉管系统中，且被AA诱导，这表明GST8-8在保护血管免受氧化应激方面起关键作用，因此可能参与动脉粥样硬化形成过程。
