Yamamoto H, Watanabe T, Mizuno H, Endo K, Fukushige J, Hosokawa T, Kazusaka A, Fujita S
Medicinal Safety Research Laboratories, Sankyo Co., Ltd., Tokyo, Japan.
Free Radic Res. 2001 Jan;34(1):69-80. doi: 10.1080/10715760100300071.
The Long-Evans Cinnamon (LEC) rats, due to a genetic defect, accumulate excess copper (Cu) in the liver in a manner similar to patients with Wilson's disease and spontaneously develop acute hepatitis with severe jaundice. In this study we examined the protective effect of DL-alpha-Lipoic acid (LA) against acute hepatitis in LEC rats. LA was administered to LEC rats by gavage in doses of 10, 30 and 100 mg/kg five times per week, starting at 8-weeks-old and continuing till 12-weeks-old. Although LA had little effect against the increases in serum transaminase activities, it suppressed the loss of body weight and prevented severe jaundice in a dose-dependent manner. Antioxidant system analyses in liver showed that LA treatment significantly suppressed the inactivations of catalase and glutathione peroxidase, and the induction of heme oxygenase-1, an enzyme which is inducible under oxidative stress. Furthermore, LA showed dose-dependent suppressive effect against increase in nonheme iron contents of both cytosolic and crude mitochondrial fractions in a dose-dependent manner. Although at the highest dose, LA slightly suppressed the accumulation of Cu in crude mitochondrial fraction, it had no effect on the accumulation of Cu in cytosolic fraction. While LA completely suppressed the increase in lipid peroxidation (LPO) in the microsomal fraction at the highest dose, the suppressive effect against LPO in crude mitochondrial fractions was slight. From these results, it is concluded that LA has antioxidant effects at the molecular level against the development of Cu-induced hepatitis in LEC rats. Moreover, mitochondrial oxidative damage might be involved in the development of acute hepatitis in LEC rats.
长-伊文斯肉桂色（LEC）大鼠由于基因缺陷，会以类似于威尔逊病患者的方式在肝脏中蓄积过量铜（Cu），并自发发展为伴有严重黄疸的急性肝炎。在本研究中，我们检测了DL-α-硫辛酸（LA）对LEC大鼠急性肝炎的保护作用。从8周龄开始，每周5次，以10、30和100mg/kg的剂量通过灌胃给LEC大鼠施用LA，持续至12周龄。尽管LA对血清转氨酶活性的升高影响不大，但它能抑制体重减轻，并以剂量依赖的方式预防严重黄疸。肝脏中的抗氧化系统分析表明，LA处理显著抑制了过氧化氢酶和谷胱甘肽过氧化物酶的失活，以及血红素加氧酶-1的诱导，血红素加氧酶-1是一种在氧化应激下可诱导的酶。此外，LA对胞质和粗线粒体部分非血红素铁含量的增加均有剂量依赖性的抑制作用。尽管在最高剂量时，LA略微抑制了粗线粒体部分中Cu的蓄积，但对胞质部分中Cu的蓄积没有影响。虽然LA在最高剂量时完全抑制了微粒体部分脂质过氧化（LPO）的增加，但对粗线粒体部分LPO的抑制作用较小。从这些结果可以得出结论，LA在分子水平上对LEC大鼠铜诱导的肝炎发展具有抗氧化作用。此外，线粒体氧化损伤可能参与了LEC大鼠急性肝炎的发展。
