MICROCYSTINS, NATURAL ENVIRONMENTAL TOXINS

微囊藻毒素，天然环境毒素

• 批准号: 3253964
• 负责人: MARIA T RUNNEGAR
• 金额: $ 21.68万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-09-01 至 1995-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3253964
• 关键词: Cyanophyta; NAD(H) phosphate; autoradiography; calcium flux; cellular pathology; cytoskeleton; cytotoxicity; environmental toxicology; fresh water environment; gel electrophoresis; glutathione; hepatotoxin; high performance liquid chromatography; image processing; immunofluorescence technique; laboratory mouse; laboratory rat; lipid peroxides; liver function; liver toxic disorder; molecular pathology; morphology; nicotinamide adenine dinucleotide; pathology; plant extracts; radionuclides; toxicant interaction; toxin metabolism

The microcystins, a family of related heptapeptides produced by the freshwater bloom-forming cyanobacterium Microcystis aeruginosa are naturally occurring environmental toxins. They are quite potent, (LD(50)ip in mice <O.l mg/kg) and chemically stable; their hepatotoxicity is not lost on boiling, nor are they inactivated by ordinary potable water treatment, thereby posing a threat to public health. An epidemiological study has shown that the presence of toxic peptides in the water supply correlated with increased liver damage in the population. Although the liver lesions caused by microcystin have been well described, the mechanism by which these peptide toxins act at the molecular or cellular level is not known. The overall purpose of this proposal is to elucidate the mechanism by which the microcystins cause liver damage. The specific work planned follows from the work done by the PI in Australia. It is known that microcystin is taken up by isolated hepatocytes, and that when administered to animals, it rapidly accumulates in the liver. (1) It is planned here to look at the transport, distribution (particularly intrahepatically), and metabolic fate of the toxin, using the easily prepared and well characterized (125)I-labeled derivative of microcystin. This will be correlated with the pathological changes found in animals following administration of microcystin. (2) The possibility that microcystin toxicity in vivo is mediated by an effect on non-parenchymal liver cells will be studied. Previous work has shown that microcystin causes changes in isolated hepatocytes. From this, two specific aims arise. These are: (3) to study the interaction of microcystin with the cytoskeleton, and (4) to characterize metabolic changes, especially changes in glutathione and calcium homeostasis. A variety of models will be employed: whole animals, isolated perfused livers, freshly isolated and cultured hepatocytes, endothelial cells. The work will be done in the laboratory of the co-PI, where all these models are in use for other liver studies. The results obtained from all these approaches will reconcile the hepatotoxicity in animals of these toxins with the changes the toxins cause in isolated hepatocytes.

微囊藻毒素是由微囊藻毒素产生的相关七肽家族 淡水水华形成蓝藻铜绿微囊藻是 自然产生的环境毒素。它们非常有效，(LD(50)ip 在小鼠中<0.1mg/kg)且化学稳定；它们的肝毒性并未消失 煮沸时，它们也不会通过普通饮用水处理而失活， 从而对公众健康构成威胁。一项流行病学研究表明 研究表明，供水中有毒肽的存在与 随着人群肝损伤的增加。虽然肝脏有病变 微囊藻毒素引起的机制已得到很好的描述 这些肽毒素在分子或细胞水平上的作用尚不清楚。 该提案的总体目的是阐明机制 微囊藻毒素会导致肝脏损伤。具体工作计划如下 PI 在澳大利亚所做的工作。据了解，微囊藻毒素被服用 由分离的肝细胞产生，当给予动物时，它 迅速积聚在肝脏中。 (1) 计划在这里查看 运输、分布（特别是肝内）和代谢命运 毒素的分析，使用易于制备和充分表征的 (125)I-标记的微囊藻毒素衍生物。这将与 动物给药后发现的病理变化 微囊藻毒素。 (2) 微囊藻毒素体内毒性的可能性是 将研究对非实质肝细胞的影响所介导的。 先前的工作表明，微囊藻毒素会导致分离的 肝细胞。由此产生了两个具体目标。它们是：（3）学习 微囊藻毒素与细胞骨架的相互作用，以及（4） 表征代谢变化，特别是谷胱甘肽和 钙稳态。将采用多种模型：整个动物、 分离的灌注肝脏、新鲜分离和培养的肝细胞、 内皮细胞。这项工作将在联合 PI 的实验室中完成， 所有这些模型都用于其他肝脏研究。结果 从所有这些方法中获得的结果将调和肝毒性 动物体内这些毒素以及这些毒素在隔离中引起的变化 肝细胞。