Cai Lu
Department of Medicine, Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY; Department of Toxicology, School of Preventive Medicine, Jilin University, Changchun, People's Republic of China.
Nonlinearity Biol Toxicol Med. 2004 Apr;2(2):89-103. doi: 10.1080/15401420490464367.
Metallothioneins (MTs) are a group of intracellular metal-binding and cysteine-enriched proteins and are highly inducible in many tissues in response to various types of stress. Although it mainly acts as a regulator of metal homeostasis such as zinc and copper in tissues, MT also acts as a potent antioxidant and adaptive (or stress) protein to protect cells and tissues from oxidative stress. Diabetes affects many Americans and other populations, and its development and toxic effect on various organs have been attributed to increased oxidative stress. Studies showed that zinc-induced or genetically enhanced pancreatic MT synthesis prevented diabetes induced by chemicals such as streptozotocin and alloxan, and zinc pretreatment also prevented spontaneously developed diabetes. Since diabetic complications are the consequences of organ damage caused by diabetic hyperglycemia and hyperlipidemia through oxidative stress, whether MT in nonpancreatic organs also provides a preventive effect on diabetic toxicity has been recently investigated. We demonstrated that overexpression of cardiac MT significantly prevented diabetes-induced cardiomyopathy. Likewise, overexpression of renal MT also prevented diabetes-induced renal toxicity. In addition, we also found that MT as an adaptive protein is overexpressed in several organs in response to diabetes. Therefore, the biological importance of diabetes-induced MT in diabetic complications and subsequent other pathogenesis was further explored. We found that diabetes-induced hepatic and renal MT synthesis was accompanied by a significant prevention of endotoxin-induced hepatic toxicity and cisplatin-induced renal toxicity. These studies suggest that MT as an adaptive protein can prevent both diabetes development and its complications or subsequent suffered other pathogenic injury.
金属硫蛋白（MTs）是一类细胞内金属结合且富含半胱氨酸的蛋白质，在许多组织中，它们能对各种应激作出高度诱导反应。尽管MT主要作为组织中锌和铜等金属稳态的调节因子发挥作用，但它也作为一种强大的抗氧化剂和适应性（或应激）蛋白，保护细胞和组织免受氧化应激的影响。糖尿病影响着许多美国人及其他人群，其发展过程以及对各个器官的毒性作用都被归因于氧化应激的增加。研究表明，锌诱导或基因增强的胰腺MT合成可预防由链脲佐菌素和四氧嘧啶等化学物质诱导的糖尿病，锌预处理还可预防自发发生的糖尿病。由于糖尿病并发症是糖尿病性高血糖和高血脂通过氧化应激导致器官损伤的后果，非胰腺器官中的MT是否也能对糖尿病毒性起到预防作用，最近已得到研究。我们证明，心脏MT的过表达显著预防了糖尿病诱导的心肌病。同样，肾脏MT的过表达也预防了糖尿病诱导的肾脏毒性。此外，我们还发现，作为适应性蛋白的MT在多个器官中因糖尿病而过度表达。因此，我们进一步探讨了糖尿病诱导的MT在糖尿病并发症及后续其他发病机制中的生物学重要性。我们发现，糖尿病诱导的肝脏和肾脏MT合成伴随着对内毒素诱导的肝脏毒性和顺铂诱导的肾脏毒性的显著预防作用。这些研究表明，MT作为一种适应性蛋白，可以预防糖尿病的发展及其并发症或后续遭受的其他致病损伤。
