Glutathione depletion enhances subanesthetic halothane hepatotoxicity in guinea pigs.
Glutathione depletion enhances subanesthetic halothane hepatotoxicity in guinea pigs.
复制标题
谷胱甘肽消耗会增强豚鼠亚麻醉氟烷的肝毒性。
DOI：
10.1097/00000542-199210000-00016
复制
发表时间：
1992
期刊：
影响因子：
8.8
通讯作者：
Hall,PM
中科院分区：
文献类型：
--
作者：
Lind,RC;Gandolfi,AJ;Hall,PM
还原型谷胱甘肽在保护肝脏免受氟烷氧化生物转化过程中产生的反应性酰基氯中间体的影响方面具有潜在作用。谷氨酸在维持受损细胞的完整性方面也很重要。因此，在雄性远交系Hartley豚鼠中研究了肝脏谷胱甘肽浓度降低对氟烷代谢中间产物与肝脏蛋白质和脂质共价结合的影响以及由此产生的肝损伤。动物注射1.6 g。kg-1 dl-丁硫氨酸-S，R-亚砜亚胺，以在暴露于0.1%（亚麻醉剂）氟烷4 h（吸入氧分压分数= 0.40）前24 h耗尽肝脏谷胱甘肽或溶剂对照溶液。在氟烷暴露时，丁硫克百威亚砜预处理可使肝脏谷胱甘肽浓度降低85%，而不会影响氟烷生物转化的程度或引起肝损伤。谷胱甘肽耗竭导致有机氟水平显着增加共价结合到肝蛋白质，但不是脂质氟烷暴露后。谷胱甘肽耗竭的动物也表现出显着增强氟烷暴露后的肝毒性;血浆异柠檬酸脱氢酶活性是25倍，比观察到的增加48小时后，在用溶剂加氟烷处理的动物暴露，肝损伤的发生率和严重程度显着更大，如观察到的光显微镜检查组织暴露后96小时。这些发现与先前提出的豚鼠氟烷相关肝毒性机制一致，并表明肝脏谷胱甘肽状态可能在患者对氟烷诱导的肝损伤的易感性中发挥重要作用。
Reduced glutathione has a potential role in protecting the liver against the reactive acyl acid chloride intermediate generated during the oxidative biotransformation of halothane. Glutathione is also important in maintaining the integrity of an injured cell. Thus, the effect of decreased hepatic glutathione concentrations on covalent binding of halothane metabolic intermediates to hepatic protein and lipid and the resultant hepatic injury were investigated in male, outbred Hartley guinea pigs. The animals were injected with either 1.6 g. kg-1 dl-buthionine-S, R-sulfoximine to deplete hepatic glutathione or vehicle-control solution 24 h before exposure to 0.1%(subanesthetic) halothane for 4 h (fractional inspired oxygen tension= 0.40). Buthionine sulfoximine pretreatment depleted liver glutathione concentrations by 85% at the time of halothane exposure, without affecting the degree of halothane biotransformation or causing hepatic injury. Glutathione depletion caused a significant increase in the level of organic fluorine covalently bound to hepatic protein but not lipid after halothane exposure. Glutathione-depleted animals also exhibited a significant enhancement of hepatotoxicity after halothane exposure; plasma isocitrate dehydrogenase activity was 25-fold greater than the increase observed 48 h after exposure in animals treated with vehicle plus halothane, and the incidence and severity of hepatic injury were significantly greater, as observed by light microscopic examination of tissue 96 h after exposure. These findings are in agreement with a previously proposed mechanism of halothane-associated hepatotoxicity in guinea pigs and indicate that hepatic glutathione status may play an important role in the susceptibility of patients to halothane-induced liver injury.