Carbon tetrachloride-induced hepatotoxicity: studies in developing rats and protection by zinc

This investigation was designed to evaluate carbon tetrachlorid (CCl4)-induced hepatotoxicity in developing rats and in adult rats pretreated with zinc. Hepatotoxicity of CCl4 in rats as young as 4 days of age was similar to that in adults. However, CCl4 metabolism, measured by in vitro binding of 14CCl4 to hepatic microsomal protein and lipid, was significantly lower in 4- and 14-day old rats than in adults. The sensitivity of young animals to CCl4 toxicity may be due to metabolic ketosis since blood concentrations of acetoacetate were 3-5 times higher in young rats than in adult animals. It has previously been shown that adult rats are more sensitive to CCl4 toxicity when they are in the ketonic state. The protection from CCl4 toxicity that was afforded adult rats pretreated with zinc was determined to be independent of the effect of zinc on CCl4 metabolism. Since treatment with zinc results in a large increase in hepatic concentration of metallothionein and that some product of 14CCl4 appeared to bind to zinc-induced metallothionein, it was suggested that metallothionein may protect against CCl4-induced liver damage by sequestering reactive metabolites of CCl4. These studies represent two examples of how the toxicity of a chemical whose toxicity is mediated via a metabolite can be modified by factors independent of metabolic activation.