权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Mechanism of cytotoxicity of Lysosphinogolipids, Especially Those of Impairment of Cellular Respiration and Their "Detoxication"

溶磷脂的细胞毒性机制，特别是细胞呼吸损伤及其“解毒”机制

基本信息

批准号：
01570461
负责人：
IGISU Hideki
金额：
$ 1.41万
依托单位：
University of Occupational and Environmental Health
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1989
资助国家：
日本
起止时间：
1989 至 1990
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-01570461/
关键词：
Lysosphingolipid Psychosine Galactosylsphingosine Glucosylsphingosine Sphingosine Lipidosis Cell respiration Albumin

项目摘要

Although enzymatic defects have been established in most sphingolipidoses, it has not been defined how the enzumatic defect is related to the pathophysiology of the disorder. Possible involvement of endogenous "toxins" have been suspected. In Krabbe disease there is ample evidence for such a hypothesis ; psychosine (galactosylsphingosine), a toxic lipid and a natural substrate of the missing enzyme, appears to play an important role in causing the devastating pathology. Similar mechanism may be present in other diseases such as Gaucher or Tay-Sachs disease.We found that galactosylsphingosine, glucosylsphingosine and sphingosine all inhibit cytochrome c oxidase (COX) in mitochondria. However, such inhibitory effects were not seen when COX was purified. When COX was reconstituted with a phospholipid, clear inhibitory effects were noted, suggesting that the inhibition of COX was caused by perturbation of the environment of the enzyme in inner membrane of mitochondria. On the other hand, effects of these lysosphingoslipids were all abolished by albumin. Using gel filtration or gel equilibrium analysis, albumin was found to have a high affinity against psychosine. Effects of albumin did not differ among three lysolipids examined. Thus, the large capacity of albumin to bind these lipids seems to underlie the "detoxicating" actions of albumin and these suggest possible use of albumin for the treatment of sphingolipidoses.Since ammonia and acrylamide, which may be regarded as "endogenous toxins", can also impair energy metabolism, attention to energy metabolism and its enzymes may be rewarding in the study of endogenous neurotoxic substances.

虽然在大多数鞘磷脂疾病中已经建立了酶缺陷，但酶缺陷如何与疾病的病理生理学相关还没有被定义。怀疑可能与内源性“毒素”有关。在Krabbe病中，有足够的证据支持这一假说；精神苷(半乳糖鞘氨醇)是一种有毒的脂质，也是缺失酶的自然底物，似乎在导致这种毁灭性的病理过程中发挥了重要作用。类似的机制也可能存在于其他疾病，如高雪病或泰-萨克斯病。我们发现，半乳糖鞘氨醇、葡萄糖鞘氨醇和鞘氨醇都能抑制线粒体中的细胞色素C氧化酶(COX)。而纯化的COX则未见这种抑制作用。当COX与磷脂重组时，有明显的抑制作用，提示COX的抑制是由于线粒体内膜酶环境的扰动所致。另一方面，这些溶鞘糖脂的作用都被白蛋白消除。通过凝胶过滤或凝胶平衡分析，发现白蛋白对心磷脂有很高的亲和力。白蛋白的作用在所研究的三种溶质脂之间没有差别。因此，白蛋白与这些脂类结合的大容量似乎是白蛋白解毒作用的基础，这表明白蛋白可能用于治疗鞘磷脂。由于氨和丙烯酰胺可能被视为“内源性毒素”，也会损害能量代谢，关注能量新陈代谢及其酶可能对内源性神经毒性物质的研究有所裨益。