Burk R F, Lane J M, Patel K
J Clin Invest. 1984 Dec;74(6):1996-2001. doi: 10.1172/JCI111621.
CCl4 exerts its toxicity through its metabolites, including the free radicals CCl3. and CCl(3)00.. Oxygen strongly inhibits the hepatic cytochrome P-450-mediated formation of CCl3. from CCl4 and promotes the conversion of CCl3. to CCl(3)00.. 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 (Burk, R.F., K. Patel, and J.M. Lane, 1983, Biochem. J., 215:441-445). 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 in O2 tension caused a fall in CHCl3 production, which indicated that it decreased CCl3.. 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. These results indicate that 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. They suggest that hyperbaric O2 might decrease free radical formation in the liver in vivo and promote formation of CCl(3)00. from CCl3.. 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 two atmospheres of 100% O2 produced much less CHCl3 and ethane than rats in air. This strongly suggests that hyperbaric O2 is decreasing free radical formation from CCl4 and/or promoting the formation of CCl(3)00. from CCl3.. These results provide the rationale for the use of hyperbaric O2 in the treatment of CCl4 ingestion.
四氯化碳通过其代谢产物发挥毒性作用，这些代谢产物包括自由基三氯甲基（CCl3.）和三氯甲基过氧自由基（CCl(3)00.）。氧气强烈抑制肝细胞色素P - 450介导的由四氯化碳生成三氯甲基的过程，并促进三氯甲基向三氯甲基过氧自由基的转化。这两种自由基都会通过引起脂质过氧化反应以及与细胞结构共价结合来损伤肝细胞。在有氧条件下，一种依赖还原型谷胱甘肽（GSH）的机制可以保护肝微粒体膜免受四氯化碳诱导的损伤，但在无氧条件下则不能（伯克，R.F.，K. 帕特尔，和J.M. 莱恩，1983年，《生物化学杂志》，215:441 - 445）。本实验使用大鼠肝微粒体来研究肝脏中发现的氧分压以及谷胱甘肽对四氯化碳诱导的共价结合和脂质过氧化反应的影响。使用了补充有烟酰胺腺嘌呤二核苷酸磷酸（NADPH）的微粒体系统。将四氯化碳或14C标记的四氯化碳加入到装有该系统的密封烧瓶中，在20分钟后测量三氯甲烷的生成量、硫代巴比妥酸反应性物质（脂质过氧化反应的一个指标）以及14C的共价结合情况。研究了0%、1%、3%、5%和21%的氧分压。氧分压升高导致三氯甲烷生成量下降，这表明它减少了三氯甲基的生成。在任何氧分压下，谷胱甘肽对三氯甲烷的生成均无显著影响。随着氧分压从1%升高到21%，脂质过氧化反应和14C的共价结合逐渐减少。添加谷胱甘肽可同时降低脂质过氧化反应和共价结合，但在较高氧分压下比在较低氧分压下效果更好。这些结果表明，肝脏小叶中心区域存在的低氧分压有利于将四氯化碳转化为无法通过依赖谷胱甘肽的机制解毒的自由基产物。它们提示高压氧可能会减少体内肝脏中自由基的形成，并促进由三氯甲基生成三氯甲基过氧自由基。这应该会减少四氯化碳诱导的脂质过氧化反应和肝脏损伤。给大鼠腹腔注射四氯化碳（2.5毫升/千克）后，在代谢室中对其进行研究。测量了三氯甲烷和乙烷的生成量，后者是脂质过氧化反应的一个指标。处于两个大气压100%氧气环境中的大鼠产生的三氯甲烷和乙烷比处于空气中的大鼠少得多。这有力地表明高压氧正在减少四氯化碳产生的自由基形成和/或促进由三氯甲基生成三氯甲基过氧自由基。这些结果为高压氧用于治疗四氯化碳摄入提供了理论依据。
