OUTPUTS OF HEPATIC COPPER AND CADMIUM STIMULATED BY TETRATHIOMOLYBDATE (TTM) INJECTION IN LONG-EVANS CINNAMON (LEG) RATS PRETREATED WITH CADMIUM, AND IN FISCHER RATS PRETREATED WITH COPPER AND CADMIUM

The Long-Evans Cinnamon (LEG) rat, an inbred mutant rat derived from t he Long-Evans strain, is characterized by spontaneous hepatitis due to gross accumulation of hepatic Cu. The accumulation, accompanied by ma rked induction of metallothionein (MT), is believed to be due to the i nherent lack of output of Cu into the bile duct and blood vessels. In this study, the acute effect of tetrathiomolybdate (TTM), a chelator f or output of hepatic Cu and Cd in LEC rats treated with Cd, was invest igated. 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 anesthes ia. The TTM injection rapidly stimulated biliary excretions of Cu (at a mu g/ml level) and Cd (at a ng/ml level). Furthermore, Cu and Cd con centrations were increased in serum sampled 60 min after the TTM injec tion. The increase of biliary Cu excretion was not accompanied by incr eased 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 mu g/g in LEC and Fischer rats, respectively. The hep atic Cd concentration was not decreased by TTM treatment. Hepatic MT a nd Cu, but not Cd, concentrations in the MT fraction were also reduced by TTM injection. Our results showed that TTM can rapidly remove Cu f rom MT to increase bile and blood Cu levels. The output of Cd stimulat ed by TTM injection may be related to MT reduction resulting from remo val of MT-bound Cu. Our results indicate that to avoid the toxic effec t of Cu, TTM injection is an effective initial treatment, although it remains to be established how metals, including Cu, are finally metabo lized. (C) 1997 Elsevier Science Ireland Ltd.