tetrathiomolybdate and Chemical-and-Drug-Induced-Liver-Injury

The Long-Evans Cinnamon (LEC) rat, an inbred mutant rat derived from the Long-Evans strain, is characterized by spontaneous hepatitis due to gross accumulation of hepatic Cu. The accumulation, accompanied by marked induction of metallothionein (MT), is believed to be due to the inherent lack of output of Cu into the bile duct and blood vessels. In this study, the acute effect of tetrathiomolybdate (TTM), a chelator for output of hepatic Cu and Cd in LEC rats treated with Cd, was investigated. Female LEC rats were injected subcutaneously with Cd (Cd; 1.0 mg/kg) to induce Cd, Cu-MT. Fischer rats were treated with Cd (Cd; 1.0 mg/kg) and Cu (Cu; 3.0 mg/kg). Forty-eight hours after the injections of metals, TTM (5 mg/kg bw) was injected intravenously under anesthesia. The TTM injection rapidly stimulated biliary excretions of Cu (at a microgram/ml level) and Cd (at a ng/ml level). Furthermore, Cu and Cd concentrations were increased in serum sampled 60 min after the TTM injection. The increase of biliary Cu excretion was not accompanied by increased biliary excretion of MT. The TTM injection caused the hepatic Cu concentrations to decrease from 306 +/- 2 to 262 +/- 12 and from 43 +/- 6 to 20 +/- 5 micrograms/g in LEC and Fischer rats, respectively. The hepatic Cd concentration was not decreased by TTM treatment. Hepatic MT and Cu, but not Cd, concentrations in the MT fraction were also reduced by TTM injection. Our results showed that TTM can rapidly remove Cu from MT to increase bile and blood Cu levels. The output of Cd stimulated by TTM injection may be related to MT reduction resulting from removal of MT-bound Cu. Our results indicate that to avoid the toxic effect of Cu, TTM injection is an effective initial treatment, although it remains to be established how metals, including Cu, are finally metabolized.

Topics: Animals; Bile; Cadmium; Ceruloplasmin; Chemical and Drug Induced Liver Injury; Copper; Female; Injections, Intravenous; Liver; Metallothionein; Molybdenum; Rats; Rats, Inbred F344; Rats, Inbred Strains