OXIDANT INJURY TO HEPATIC MITOCHONDRIA IN PATIENTS WITH WILSONS-DISEASE AND BEDLINGTON TERRIERS WITH COPPER TOXICOSIS
OXIDANT INJURY TO HEPATIC MITOCHONDRIA IN PATIENTS WITH WILSONS-DISEASE AND BEDLINGTON TERRIERS WITH COPPER TOXICOSIS
复制标题
DOI：
10.1016/0016-5085(94)90822-2
复制
发表时间：
1994-12-01
期刊：
影响因子：
29.4
通讯作者：
NEUSCHWANDERTETRI, BA
中科院分区：
文献类型：
--
作者：
SOKOL, RJ;TWEDT, D;NEUSCHWANDERTETRI, BA
背景/目的：铜超载会导致患有威尔逊氏病的人类和患有铜中毒的贝灵顿梗犬的肝损伤；然而，人们对肝损伤的机制知之甚少。这项研究的目的是确定肝线粒体的氧化剂（自由基）损伤是否与自然发生的铜中毒有关。方法：在肝移植时从 3 名威尔逊病患者、8 名胆汁淤积性肝病患者和 5 名非胆汁淤积性肝病患者以及 8 名对照肝脏中获取新鲜肝脏样本。还通过开放肝脏活检从 4 只铜超载和 4 只正常贝灵顿梗犬以及 8 只对照狗中获得新鲜肝脏。分离肝线粒体和微粒体（仅限人类），并通过脂质共轭二烯和硫代巴比妥酸反应物质测量脂质过氧化。在人类中，测量了肝脏α-生育酚含量。结果：威尔逊病患者和铜超载的贝灵顿梗犬线粒体中的脂质过氧化和铜含量显着增加（P < 0.05）。威尔逊氏病患者的微粒体中脂质过氧化水平有较温和的增加。线粒体铜浓度与线粒体脂质过氧化的严重程度密切相关。威尔逊病肝脏中肝脏α-生育酚含量显着降低。结论：这些数据表明，肝线粒体是肝铜毒性的重要靶标，对肝脏的氧化损伤可能参与铜引起的损伤的发病机制。
Background/Aims: Copper overload leads to liver injury in humans with Wilson's disease and in Bedlington terriers with copper toxicosis; however, the mechanisms of liver injury are poorly understood. This study was undertaken to determine if oxidant (free radical) damage to hepatic mitochondria is involved in naturally occurring copper toxicosis. Methods: Fresh liver samples were obtained at the time of liver transplantation from 3 patients with Wilson's disease, 8 with cholestatic liver disease, and 5 with noncholestatic liver disease and from 8 control livers. Fresh liver was also obtained by open liver biopsy from 4 copper-overloaded and 4 normal Bedlington terriers and from 8 control dogs. Hepatic mitochondria and microsomes (humans only) were isolated, and lipid peroxidation was measured by lipid-conjugated dienes and thiobarbituric acid-reacting substances. In humans, liver alpha-tocopherol content was measured. Results: Lipid peroxidation and copper content were significantly increased (P < 0.05) in mitochondria from patients with Wilson's disease and copper-overloaded Bedlington terriers. More modest increases in lipid peroxidation were present in microsomes from patients with Wilson's disease. Mitochondrial copper concentrations correlated strongly with the severity of mitochondrial lipid peroxidation. Hepatic alpha-tocopherol content was decreased significantly in Wilson's disease liver. Conclusions: These data suggest that the hepatic mitochondrion is an important target in hepatic copper toxicity and that oxidant damage to the liver may be involved in the pathogenesis of copper-induced injury.