Protection of carbon tetrachloride-induced hepatotoxicity by zinc: role of metallothionein

The dose-dependent release of alanine aminotransferase and aspartate aminotransferase into plasma 24 hr following various doses of CCl₄ (ip) was markedly lower in rats pretreated for 3 days with zinc chloride (150 μmol/kg/day) than in control rats. Although this dose of zinc produced a 34% decrease in hepatic concentration of cytochrome P-450 and a 50% decrease in binding of ¹⁴C derived from ¹⁴CCl₄ to hepatic microsomal protein and lipid in vitro, prior treatment with a single injection of zinc (250 μmol/kg) resulted in protection against CCl₄ toxicity without changing P-450 concentrations or ¹⁴C binding. Administration of a single dose (250 μmol/kg) of zinc or pretreatment on 3 consecutive days with 150 μmol/kg zinc produced a 700 or 1900% increase in hepatic concentration of metallothionein (MT), respectively. Following administration of ¹⁴CCl₄ to zinc-treated rats, radioactivity was present in the same elution volume as MT following gel filtration (G-75) of liver cytosol. This suggests that MT may protect against CCl₄-induced liver damage by sequestering reactive metabolites of CCl₄.