Abstract
Support for the hypothesis that metallothionein isoforms participate in intracellular defense against reactive oxygen and nitrogen species is derived from observations that substances causing oxidative stress, such as ethanol and iron, and agents involved in inflammatory processes, such as interleukin-1 and tumour necrosis factor alpha, induce the synthesis of metallothionein. Moreover, animals deficient in metallothionein isoforms exhibit greater susceptibility to oxidative stress; metallothionein genes are transcriptionally activated in cells and tissues during oxidative stress; and over expression of metallothionein reduces the sensitivity of cells and tissues to free radical-induced injury. In this study, we have shown that the i.c.v. administration of ZnSO
4 increases the synthesis of metallothionein I mRNA and metallothionein II mRNA. In addition, the i.c.v. administration of ZnSO
4 enhances the concentration of zinc and in direct proportion the synthesis of metallothionein mRNAs. Agents known to generate free radicals and to cause oxidative stress such as 6-hydroxydopamine, iron, hydrogen peroxide, and various alcohols lead to induction of metallothionein in the hippocampal neurons in primary culture and in Chang liver cells in culture.
In view of the fact that zinc and 6-hydroxydopamine induce the level of brain metallothionein and its mRNAs and zinc and metallothionein concentrations vary in different regions of the brain, it is postulated that metallothionein may play a major role in nullifying the iron-mediated generation of free radicals and in protecting against oxidative stress in the brain. Copyright © 1996 Elsevier Science Ltd.