Carbon tetrachloride-induced lethality in mouse is prevented by multiple pretreatment with zinc sulfate

Abstract

Carbon tetrachloride (CCl₄) is commonly used as a chemical inducer of experimental liver injury. Several compounds have been demonstrated to attenuate the hepatic damage caused by sublethal doses of CCl₄. However, rescue from lethal toxicity of CCl₄ has not been reported. In the present study, we evaluated the protective effect of metallothionein (MT), an endogenous scavenger of free radicals, on CCl₄-induced lethal toxicity of mice. To induce MT production in male ddY mice, we administered Zn (as ZnSO₄) at 50 mg/kg as a once-daily subcutaneous injection for 3 days prior to a single intraperitoneal administration of 4 g/kg CCl₄. Animals were observed for mortality every 3 hr for 24 hr after CCl₄ injection. Liver damage was assessed by determining (in a subset of these mice) blood levels of alanine aminotransferase (ALT; a marker of liver injury) and liver histopathology at 6 hr after CCl₄ injection. Our results showed that three times pretreatment with Zn yielded > 40-fold induction of hepatic MT protein levels compared to control group. Zn pretreatment completely abolished the CCl₄-induced mortality of mice. We also found that pretreatment of mice with Zn significantly decreased the ALT levels and reduced the histological liver damage as assessed at 6 hr post-CCl₄. These findings suggest that prophylaxis with Zn protects mice from CCl₄-induced acute hepatic toxicity and mortality, presumably by induction of radical-scavenging MT.