Nakae D, Yamamoto K, Yoshiji H, Kinugasa T, Maruyama H, Farber J L, Konishi Y
Department of Oncological Pathology, Nara Medical University, Japan.
Am J Pathol. 1990 Apr;136(4):787-95.
Liposome-encapsulated human recombinant superoxide dismutase (LSOD) protected male rats that were pretreated with 3-methylcholanthrene from the liver necrosis produced by acetaminophen. By contrast, SOD-free liposomes, free SOD, or heat-denatured LSOD had no protective effect. Liposome-encapsulated SOD did not simply delay the onset of liver necrosis. A second dose of LSOD at 12 hours prevented the necrosis of the liver as assessed 24 hours after treatment with 500 mg/kg body weight of acetaminophen. Liposome-encapsulated human recombinant superoxide dismutase did not alter the metabolism of acetaminophen as assessed by either the rate or extent of the depletion of hepatic stores of glutathione or by the extent of the covalent binding of the metabolites of [3H]acetaminophen to total liver cell proteins. Evidence of the peroxidation of lipids in the accumulation of malondialdehyde in the livers was detected within 3 hours of the administration of acetaminophen and before the appearance of liver necrosis. Liposome-encapsulated human recombinant superoxide dismutase prevented the accumulation of malondialdehyde in parallel with the prevention of liver necrosis. Finally, LSOD also prevented the potentiation by 1,3-bis(2-chloroethyl)-1-nitrosourea of the hepatotoxicity of acetaminophen. These data document the participation of superoxide anions in the hepatotoxicity of acetaminophen in intact rats.
脂质体包裹的人重组超氧化物歧化酶（LSOD）可保护经3-甲基胆蒽预处理的雄性大鼠免受对乙酰氨基酚所致的肝坏死。相比之下，不含超氧化物歧化酶的脂质体、游离超氧化物歧化酶或热变性的LSOD均无保护作用。脂质体包裹的超氧化物歧化酶并非仅仅延迟肝坏死的发生。在给予500mg/kg体重对乙酰氨基酚治疗24小时后评估发现，在12小时给予第二剂LSOD可预防肝脏坏死。通过谷胱甘肽肝储备耗竭的速率或程度，或通过[3H]对乙酰氨基酚代谢产物与全肝细胞蛋白的共价结合程度评估发现，脂质体包裹的人重组超氧化物歧化酶不会改变对乙酰氨基酚的代谢。在给予对乙酰氨基酚后3小时内且在肝坏死出现之前，检测到肝脏中丙二醛积累存在脂质过氧化的证据。脂质体包裹的人重组超氧化物歧化酶在预防肝坏死的同时可防止丙二醛的积累。最后，LSOD还可预防1,3-双（2-氯乙基）-1-亚硝基脲增强对乙酰氨基酚的肝毒性。这些数据证明超氧阴离子参与了完整大鼠中对乙酰氨基酚的肝毒性作用。
