RELATIONSHIP OF OXYGEN AND GLUTATHIONE IN PROTECTION AGAINST CARBON TETRACHLORIDE-INDUCED HEPATIC-MICROSOMAL LIPID-PEROXIDATION AND COVALENT BINDING IN THE RAT - RATIONALE FOR THE USE OF HYPERBARIC-OXYGEN TO TREAT CARBON-TETRACHLORIDE INGESTION
RELATIONSHIP OF OXYGEN AND GLUTATHIONE IN PROTECTION AGAINST CARBON TETRACHLORIDE-INDUCED HEPATIC-MICROSOMAL LIPID-PEROXIDATION AND COVALENT BINDING IN THE RAT - RATIONALE FOR THE USE OF HYPERBARIC-OXYGEN TO TREAT CARBON-TETRACHLORIDE INGESTION
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DOI：
10.1172/jci111621
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发表时间：
1984-01-01
影响因子：
15.9
通讯作者：
PATEL, K
中科院分区：
文献类型：
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作者：
BURK, RF;LANE, JM;PATEL, K
CCL 4通过其代谢物发挥其毒性，包括自由基CCL 3和CCl 300。O2强烈抑制肝细胞色素P-450介导的从CCl 4形成CCl.ovrhdot.3，并促进CCl.ovrhdot.3转化为CCl 300。这两种自由基通过引起脂质过氧化和共价结合细胞结构来损伤肝细胞。还原型谷胱甘肽（GSH）依赖性机制可以保护肝微粒体膜在有氧条件下免受CCl 4诱导的损伤，但在厌氧条件下不受影响。使用大鼠肝微粒体进行实验，以检查在肝脏中发现的O2张力和GSH对四氯化碳诱导的共价结合和脂质过氧化的影响。使用补充NADPH的微粒体系统。将CCl 4或14 CCl 4加入到包含该系统的密封烧瓶中，在20分钟CHCl 3产生后，测量硫代巴比妥酸反应性物质（脂质过氧化的指标）和14 C的共价结合。研究了0、1、3、5和21%的O2张力。O2张力的增加导致了CHCl 3生产的下降，这表明它降低了CCl。GSH在任何O2张力下对CHCl 3的产生均无显著影响。随着O2张力从1%增加到21%，14 C的脂质过氧化和共价结合逐渐下降。GSH的加入降低了脂质过氧化和共价结合，但在较高的O2张力比在较低的。低O2张力（例如在肝脏小叶中心区域发现的低O2张力）有利于CCl 4转化为自由基产物，而自由基产物无法通过GSH依赖性机制解毒。高压O2可减少体内肝脏自由基的形成，促进CCl 300的形成。来自CCl.ovrhdot.3。这将导致减少四氯化碳诱导的脂质过氧化和肝损伤。在代谢室中研究了给予CCl 4（2.5 ml/kg）的大鼠。三氯甲烷和乙烷的生产，后者的脂质过氧化反应的指数，进行了测量。大鼠在2个大气压的100%O2产生更少的三氯甲烷和乙烷比大鼠在空气中。这强烈表明，高压O2是减少自由基形成的四氯化碳和/或促进形成的四氯化碳300。来自CCl.ovrhdot.3。这些结果提供了使用高压O2治疗CCl 4摄入的基本原理。
CCL4 exerts its toxicity through its metabolites, including the free radicals CCL.ovrhdot.3 and CCl300.. O2 strongly inhibits the hepatic cytochrome P-450-mediated formation of CCl.ovrhdot.3 from CCl4 and promotes the conversion of CCl.ovrhdot.3 to CCl300.. Both these free radicals injure the hepatocyte by causing lipid peroxidation and binding covalently to cell structures. A reduced glutathione (GSH)-dependent mechanism can protect the liver microsomal membrane against CCl4-induced damage under aerobic conditions but not under anaerobic conditions. Experiments were carried out using rat liver microsomes to examine the effect of O2 tensions found in the liver and of GSH on CCl4-induced covalent binding and lipid peroxidation. An NADPH-supplemented microsomal system was used. CCl4 or 14CCl4 was added to the sealed flask that contained the system and, after 20 min CHCl3 production, thiobarbituric acid-reactive substances (an index of lipid peroxidation) and covalent binding of 14C were measured. O2 tensions of 0, 1, 3, 5 and 21% were studied. Increases of O2 tension caused a fall in CHCl3 production, which indicated that it decreased CCl.ovrhdot.3. GSH had no significant effect on CHCl3 production at any O2 tension. Lipid peroxidation and covalent binding of 14C fell progressively as O2 tension was increased from 1 to 21%. The addition of GSH decreased both lipid peroxidation and covalent binding, but did so better at the higher O2 tensions than at the lower ones. Low O2 tensions such as are found in the centrilobular areas of the liver favor conversion of CCl4 to free radical products which cannot be detoxified by the GSH-dependent mechanism. Hyperbaric O2 might decrease free radical formation in the liver in vivo and promote formation of CCl300. from CCl.ovrhdot.3. This should result in diminished CCl4-induced lipid peroxidation and liver damage. Rats given CCl4 (2.5 ml/kg) were studied in metabolic chambers. Production of CHCl3 and ethane, the latter an index of lipid peroxidation, were measured. Rats in 2 atm of 100% O2 produced much less CHCl3 and ethane than rats in air. This strongly suggests that hyperbaric O2 is decreased free radical formation from CCl4 and/or promoting the formation of CCl300. from CCl.ovrhdot.3. These results provide the rationale for the use of hyperbaric O2 in the treatment of CCl4 ingestion.