Liver Study Unit, Omaha Veterans Affairs Medical Center, University of Nebraska Medical Center, Omaha, Nebraska, USA.
Alcohol Clin Exp Res. 2010 Feb;34(2):251-61. doi: 10.1111/j.1530-0277.2009.01088.x. Epub 2009 Nov 30.
Ethanol metabolism increases production of reactive oxygen species, including superoxide (O2(.-)) in the liver, resulting in significant oxidative stress, which causes cellular damage. Superoxide dismutase (SOD) is an antioxidant enzyme that converts superoxide to less toxic intermediates, preventing accumulation. Because the absence of SOD would confer less resistance to oxidative stress, we determined whether damage to hepatic proteolytic systems was greater in SOD(-/-) than in SOD(+/+) mice after chronic ethanol feeding.
Female wild-type (SOD(+/+)) and Cu/Zn-SOD knockout (SOD(-/-)) mice were pair-fed ethanol and control liquid diets for 24 days, after which liver injury was assessed.
Ethanol-fed SOD(-/-) mice had 4-fold higher blood ethanol, 2.8-fold higher alanine aminotransferase levels, 20% higher liver weight, a 1.4-fold rise in hepatic protein levels, and 35 to 70% higher levels of lipid peroxides than corresponding wild-type mice. While wild-type mice exhibited fatty liver after ethanol administration, SOD(-/-) mice showed no evidence of ethanol-induced steatosis, although triglyceride levels were elevated in both groups of knockout mice. Ethanol administration caused no significant change in proteasome activity, but caused lysosomal leakage in livers of SOD(-/-) mice but not in wild-type mice. Alcohol dehydrogenase activity was reduced by 50 to 60% in ethanol-fed SOD(-/-) mice compared with all other groups. Additionally, while ethanol administration induced cytochrome P450 2E1 (CYP2E1) activity in wild-type mice, it caused no such induction in SOD(-/-) mice. Unexpectedly, ethanol feeding significantly elevated total and mitochondrial levels of glutathione in SOD knockout mice compared with wild-type mice.
Ethanol-fed SOD(-/-) mice exhibited lower alcohol dehydrogenase activity and lack of CYP2E1 inducibility, thereby causing decreased ethanol metabolism compared with wild-type mice. These and other atypical responses to ethanol, including the absence of ethanol-induced steatosis and enhanced glutathione levels, appear to be linked to enhanced oxidative stress due to lack of antioxidant enzyme capacity.
乙醇代谢会增加肝脏中活性氧的产生，包括超氧阴离子（O2(-)），从而导致显著的氧化应激，造成细胞损伤。超氧化物歧化酶（SOD）是一种抗氧化酶，可将超氧阴离子转化为毒性较小的中间产物，防止其积累。由于 SOD 的缺失会降低对氧化应激的抵抗力，因此我们确定在慢性乙醇喂养后，SOD(-/-)小鼠的肝蛋白水解系统的损伤是否比 SOD(+/+)小鼠更严重。
将雌性野生型（SOD(+/+)）和 Cu/Zn-SOD 敲除（SOD(-/-)）小鼠进行配对喂养，分别给予乙醇和对照液体饮食 24 天，然后评估肝损伤。
乙醇喂养的 SOD(-/-)小鼠的血液乙醇水平高 4 倍，丙氨酸氨基转移酶水平高 2.8 倍，肝重增加 20%，肝蛋白水平升高 1.4 倍，脂质过氧化物水平升高 35%至 70%，高于相应的野生型小鼠。虽然野生型小鼠在给予乙醇后出现脂肪肝，但 SOD(-/-)小鼠没有表现出乙醇诱导的脂肪变性的迹象，尽管两组敲除小鼠的甘油三酯水平均升高。乙醇处理未显著改变蛋白酶体活性，但导致 SOD(-/-)小鼠的溶酶体泄漏，而野生型小鼠没有。与其他所有组相比，乙醇喂养的 SOD(-/-)小鼠的醇脱氢酶活性降低了 50%至 60%。此外，虽然乙醇诱导野生型小鼠的细胞色素 P450 2E1（CYP2E1）活性，但在 SOD(-/-)小鼠中没有诱导。出乎意料的是，与野生型小鼠相比，乙醇喂养显著增加了 SOD 敲除小鼠的总谷胱甘肽和线粒体谷胱甘肽水平。
与野生型小鼠相比，乙醇喂养的 SOD(-/-)小鼠的醇脱氢酶活性较低，且 CYP2E1 诱导能力缺失，从而导致乙醇代谢减少。这些和其他对乙醇的非典型反应，包括缺乏乙醇诱导的脂肪变性和增强的谷胱甘肽水平，似乎与抗氧化酶能力缺乏导致的氧化应激增强有关。
