Ichi Ikuyo, Kamikawa Chiaki, Nakagawa Tomoka, Kobayashi Keiko, Kataoka Ryoko, Nagata Eri, Kitamura Yuko, Nakazaki Chihiro, Matsura Tatsuya, Kojo Shosuke
Department of Food Science and Nutrition, Nara Women's University, Nara 630-8506, Japan.
Toxicology. 2009 Jun 30;261(1-2):33-40. doi: 10.1016/j.tox.2009.04.040. Epub 2009 Apr 24.
Ceramide is a biologically active lipid causing apoptosis in a variety of cells. In this study, we examined the effect of CCl4 on the ceramide metabolism and indicators of oxidative stress. After 12 h of oral administration of CCl4 (4 ml/kg body weight as a 1:1 mixture of CCl4 and mineral oil) to rats, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were increased. Antioxidants such as vitamins C and E were decreased in the liver and kidney. In addition, the ratio of GSH/GSSG in the liver, plasma, kidney, and brain decreased at 2h. The total ceramide in the liver significantly increased as early as 2h after CCl4 administration. After 24 and 36 h, the total ceramide in plasma and the kidney was also augmented. In the brain, the total ceramide dramatically increased at 36 h. These results suggested that the increased ceramide in plasma was transferred to the kidney and the brain. The activity of neutral sphingomyelinase (SMase), which was reported to be enhanced by the decrease of GSH, was significantly increased after CCl4 treatment in the liver, kidney, and brain. However, acid SMase activities were not increased in the liver and kidney. Thus, the activation of neutral SMase via oxidative stress induced the increase of ceramide during CCl4 intoxication in not only the liver but also other tissues. These results suggested that the excess accumulation of ceramide causes damage in other organs including the kidney and brain during fulminant hepatic failure.
神经酰胺是一种生物活性脂质，可导致多种细胞发生凋亡。在本研究中，我们检测了四氯化碳对神经酰胺代谢及氧化应激指标的影响。给大鼠口服四氯化碳（4 ml/kg体重，以四氯化碳与矿物油1:1的混合物形式）12小时后，天冬氨酸转氨酶（AST）和丙氨酸转氨酶（ALT）升高。肝脏和肾脏中的抗氧化剂如维生素C和E减少。此外，肝脏、血浆、肾脏和大脑中谷胱甘肽/氧化型谷胱甘肽（GSH/GSSG）的比值在2小时时降低。早在四氯化碳给药后2小时，肝脏中的总神经酰胺就显著增加。24小时和36小时后，血浆和肾脏中的总神经酰胺也增加。在大脑中，总神经酰胺在36小时时急剧增加。这些结果表明，血浆中增加的神经酰胺转移到了肾脏和大脑。据报道，谷胱甘肽减少会增强中性鞘磷脂酶（SMase）的活性，在四氯化碳处理后，肝脏、肾脏和大脑中的中性鞘磷脂酶活性显著增加。然而，肝脏和肾脏中的酸性鞘磷脂酶活性并未增加。因此，在四氯化碳中毒期间，不仅在肝脏，而且在其他组织中，通过氧化应激激活中性鞘磷脂酶会导致神经酰胺增加。这些结果表明，在暴发性肝衰竭期间，神经酰胺的过量积累会对包括肾脏和大脑在内的其他器官造成损害。
