THE ANTIOXIDANT PROPERTIES OF ZINC AND METALLOTHIONEIN

Support for the hypothesis that metallothionein isoforms participate i n intracellular defense against reactive oxygen and nitrogen species i s derived from observations that substances causing oxidative stress, such as ethanol and iron, and agents involved in inflammatory processe s, such as interleukin-1 and tumour necrosis factor alpha, induce the synthesis of metallothionein. Moreover, animals deficient in metalloth ionein isoforms exhibit greater susceptibility to oxidative stress; me tallothionein genes are transcriptionally activated in cells and tissu es during oxidative stress; and over expression of metallothionein red uces the sensitivity of cells and tissues to free radical-induced inju ry. In this study, we have shown that the i.c.v. administration of ZnS O4 increases the synthesis of metallothionein I mRNA and metallothione in II mRNA. In addition, the i.c.v. administration of ZnSO4 enhances t he concentration of zinc and in direct proportion the synthesis of met allothionein mRNAs. Agents known to generate free radicals and to caus e oxidative stress such as 6-hydroxydopamine, iron, hydrogen peroxide, and various alcohols lead to induction of metallothionein in the hipp ocampal 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 c oncentrations vary in different regions of the brain, it is postulated that metallothionein may play a major role in nullifying the iron-med iated generation of free radicals and in protecting against oxidative stress in the brain. Copyright (C) 1996 Elsevier Science Ltd.