Induction of Hepatic Metallothionein by Mitochondrial Oxidative Stress in Mice

Abstract

The effects of three inhibitors of mitochondrial respiratory functions on the induction of metallothionein (MT) in the liver were investigated in mice. C57BL/6 mice were injected subcutaneously with sodium azide, atractyloside, or malonic acid and were analyzed for the hepatic levels of thiobarbituric acid-reactive substances (TBARS) and MT. Sodium azide and atractyloside increased the hepatic MT level transiently around 6 and 12 hr, respectively, after the injection. Malonic acid significantly increased the MT level even at 3 hr and the increase continued until at least 24 hr after the injection. In all three cases, the changes in hepatic MT level showed almost the same patterns as those of TBARS with respect to both kinetics and magnitude. The increases in both TBARS and MT in the liver due to malonic acid were inhibited by about 90% by preinjection of succinic acid. These results suggest that the inhibitors of mitochondrial respiratory functions directly affect the mitochondria of hepatic cells, causing the production of reactive oxygen species, and consequently resulting in the induction of MT in mice.