Kanazawa K
Department of Agricultural Chemistry, Kobe University, Japan.
Adv Exp Med Biol. 1991;289:237-53. doi: 10.1007/978-1-4899-2626-5_17.
Hepatic dysfunction caused by oxidative stress when secondary peroxidation products were administered orally was investigated in rat. In serum at 24 hr after the administration of secondary products, the contents of lipid peroxides reached a maximum, the level of tocopherol reached a minimum, and the transaminase activities were elevated. In the liver, the lipid peroxide contents were kept high between 6 and 24 hr and tocopherol level was kept low between 15 and 48 hr after the does. Therefore, the hepatic oxidative stress was most severe around 15 hr after the dose. Dysfunction in the liver having oxidative stress was then made clear. One was a disturbance in synthetic system of glucose 6-phosphate. The decreases in activities of phosphoglucomutase and glucokinase reduced a level of glucose 6-phosphate, which suppressed the supply of NADPH in pentose cycle, while the NADPH was consuming well for detoxification of endogenous lipid peroxides. Another was specific inactivations of mitochondrial succinate dehydrogenase and aldehyde dehydrogenase. A third was the depletion of CoASH, which induced the decreases in activities of citrate cycle and lipogenesis. The other was a formation of lipofuscin. Even after the liver was recovering from the oxidative stress, the liver was getting hypertrophy and lipofuscin was accumulating. To make the cause of hepatic dysfunction clear, it was examined whether the incorporated secondary products in the liver could directly attack the enzymes or not. A reasonable amount of secondary products present in the liver was estimated, and then the amount of secondary products was added in hepatic subcellular organelles in vitro. It was found that mitochondrial NAD-dependent aldehyde dehydrogenase, glucokinase, and CoASH were directly attacked and inactivated by the incorporated secondary products in the liver. Thus, a part of dietary secondary products was incorporated into liver, and was not detoxified, but injured the enzymes and CoASH. Then it resulted in lipofuscin formation.
在大鼠中研究了口服次级过氧化产物时由氧化应激引起的肝功能障碍。给予次级产物后24小时，血清中脂质过氧化物含量达到最高，生育酚水平达到最低，转氨酶活性升高。在肝脏中，给药后6至24小时脂质过氧化物含量保持较高，15至48小时生育酚水平保持较低。因此，给药后约15小时肝脏氧化应激最为严重。然后明确了存在氧化应激的肝脏功能障碍。一是葡萄糖6-磷酸合成系统紊乱。磷酸葡萄糖变位酶和葡萄糖激酶活性降低，导致葡萄糖6-磷酸水平降低，抑制了戊糖循环中NADPH的供应，而NADPH因内源性脂质过氧化物的解毒而大量消耗。另一个是线粒体琥珀酸脱氢酶和醛脱氢酶的特异性失活。第三个是辅酶A的消耗，这导致柠檬酸循环和脂肪生成活性降低。另一个是脂褐素的形成。即使肝脏从氧化应激中恢复后，肝脏仍在肥大，脂褐素在积累。为了明确肝功能障碍的原因，研究了肝脏中摄入的次级产物是否能直接攻击酶。估计了肝脏中存在的合理量的次级产物，然后在体外将次级产物的量添加到肝亚细胞器中。发现肝脏中摄入的次级产物直接攻击并使线粒体NAD依赖性醛脱氢酶、葡萄糖激酶和辅酶A失活。因此，一部分膳食次级产物被摄入肝脏，未被解毒，而是损伤了酶和辅酶A。然后导致了脂褐素的形成。
