INDUCTION OF METALLOTHIONEIN AS AN ADAPTIVE MECHANISM AFFECTING THE MAGNITUDE AND PROGRESSION OF TOXICOLOGICAL INJURY

Pretreatment of rats with low doses of Cd produces adaptive tolerance to a subsequent high dose of Cd-induced lethality, thus shifting the d ose-response curve to the right. Cd pretreatment of animals also prote cts against the hepatotoxicity produced by high doses of Cd. This prot ection is attributable to the 10- to 50-fold induction of hepatic meta llothionein (MT) by Cd pretreatment. As a result hepatic subcellular d istribution of Cd is significantly altered, with more Cd bound to MT i n the cytosol and a concomitant reduction of Cd in other critical orga nelles. In addition MT-transgenic animals are more resistant, whereas MT-null mice are more sensitive than controls to Cd-induced lethality and hepatotoxicity. This further demonstrates that MT is important in Cd detoxication. Induction of hepatic MT by zinc also protects mice fr om carbon tetrachloride (CCl4)-induced liver injury, with more C-14-CC l4 bound to MT in the cytosol. MT-null mice are more sensitive to CCl4 -induced hepatotoxicity, which supports the hypothesis that induction of MT also plays a protective role for nonmetallic chemicals. These re sults indicate that MT is a part of cellular adaptive mechanisms affec ting the magnitude and progression of toxic insults from metals such a s Cd as well as from organic chemicals such as CCl4.