Carbon tetrachloride (CCl
4) is a well-known hepatotoxic chemical. Exposure to CCl
4 produces free radicals, which induce oxidative stress and cause hepatic injury. We demonstrated previously that pretreatment with zinc (Zn), which induces metallothionein (MT) expression, prevents CCl
4-induced lethal toxicity in a dose-dependent manner. While MT has been suggested as a possible hepatoprotective protein, its mechanism of protection remains unknown. In the current study, we evaluated the protective mechanism of MT, an endogenous scavenger of free radicals, against CCl
4-induced toxicity through subcutaneous administration of 50 mg/kg Zn (as ZnSO
4) once daily for three consecutive days, prior to a single intraperitoneal injection of 4 g/kg CCl
4 in male ddY mice. Our results showed that Zn pretreatment significantly decreased aspartate aminotransferase and total cholesterol levels, 6-hr after CCl
4 injection, as well as lipid peroxidation. Moreover, CCl
4-induced hepatic calcium level was downregulated by pretreatment with Zn while Zn-induced MT expression decreased by more than 500 µg/g liver (43%) in the Zn + CCl
4-treated group, implying that MT was consumed by CCl
4-induced free radicals. These findings suggest that prophylaxis with Zn protects mice from CCl
4-induced acute hepatotoxicity, presumably by inducing the expression of free radical-scavenging MT.
View full abstract