Shertzer H G, Sainsbury M
Department of Environmental Health, University of Cincinnati Medical Center, OH 45267-0056, USA.
Food Chem Toxicol. 1988 Jun;26(6):517-22. doi: 10.1016/0278-6915(88)90004-x.
The influence of 5,10-dihydroindeno[1,2-b]indole (indenoindole) on carbon tetrachloride (CCl4)-mediated hepatotoxicity and lipid peroxidation were examined. Indenoindole (25 mg/kg body weight) ameliorated the increase in liver enzymes appearing in the plasma 24 hr after CCl4 administration, with about a 63% reduction for alanine transaminase, 56% for ornithine transcarbamylase and 84% for alkaline phosphatase. Indenoindole also partially prevented, in a dose-dependent fashion, the decrease in hepatic cytochromes P-450, total tissue reducing equivalents and hepatic ascorbate levels resulting 4 hr after CCl4 administration. In a homogeneous chemical system consisting of purified soybean phospholipid substrate in chlorobenzene, azobisisobutyronitrile-initiated lipid peroxidation was inhibited by indeno-indole, with 50% inhibition occurring at about 17 microM. Inhibition by indenoindole of iron-ascorbate-initiated lipid peroxidation in aqueous buffer containing phospholipid vesicles was about tenfold more efficient, with 50% inhibition occurring at about 1.5 microM. Presumably, this was due to the increased concentration of indenoindole in the membrane of the phospholipid vesicle. The efficiency of inhibition of lipid peroxidation was in the order of indenoindole = butylated hydroxytoluene (BHT) greater than alpha-tocopherol much greater than indole greater than indene. These 50% inhibition values of lipid peroxidation for these compounds were similar in an assay system composed of NADPH-fortified mouse-liver microsomes initiated with CCl4. For indenoindole, the 50% inhibition value (1.3 microM) was more than two orders of magnitude less than the spectral binding constant for indenoindole to mouse-liver cytochrome P-450 (Kd = 236 microM), implying that the partial inhibition of metabolic activation of CCl4 was not responsible for the inhibition of lipid peroxidation observed with indenoindole in this system. It appears that indenoindole may trap reactive radicals and inhibit lipid peroxidation in vitro. Regardless of whether inhibition is at the level of scavenging CCl4 metabolite radicals, or lipid radicals in membranes, radical trapping provides a plausible mechanism by which this compound inhibited CCl4 hepatotoxicity.
研究了5,10 - 二氢茚并[1,2 - b]吲哚（茚并吲哚）对四氯化碳（CCl4）介导的肝毒性和脂质过氧化的影响。茚并吲哚（25毫克/千克体重）改善了CCl4给药24小时后血浆中出现的肝酶升高，丙氨酸转氨酶降低约63%，鸟氨酸转氨甲酰酶降低56%，碱性磷酸酶降低84%。茚并吲哚还以剂量依赖的方式部分预防了CCl4给药4小时后导致的肝细胞色素P - 450、总组织还原当量和肝抗坏血酸水平的降低。在由氯苯中的纯化大豆磷脂底物组成的均相化学体系中，偶氮二异丁腈引发的脂质过氧化受到茚并吲哚的抑制，在约17微摩尔时出现50%的抑制。茚并吲哚对含磷脂囊泡的水性缓冲液中铁 - 抗坏血酸引发的脂质过氧化的抑制效率约高十倍，在约1.5微摩尔时出现50%的抑制。据推测，这是由于茚并吲哚在磷脂囊泡膜中的浓度增加。脂质过氧化抑制效率的顺序为茚并吲哚 = 丁基化羟基甲苯（BHT）＞α - 生育酚＞吲哚＞茚。在由CCl4引发的NADPH强化小鼠肝微粒体组成的测定系统中，这些化合物的脂质过氧化50%抑制值相似。对于茚并吲哚，50%抑制值（1.3微摩尔）比茚并吲哚与小鼠肝细胞色素P - 450的光谱结合常数（Kd = 236微摩尔）低两个多数量级，这意味着茚并吲哚对CCl4代谢活化的部分抑制不是该系统中观察到的脂质过氧化抑制的原因。看来茚并吲哚可能在体外捕获活性自由基并抑制脂质过氧化。无论抑制是在清除CCl4代谢物自由基还是膜中脂质自由基的水平上，自由基捕获都提供了一种合理的机制，通过该机制该化合物抑制了CCl4肝毒性。
