Lai Y R, Sugawara N
Department of Public Health, School of Medicine, Sapporo Medical University, Japan.
Toxicology. 1997 Jun 6;120(1):47-54. doi: 10.1016/s0300-483x(97)03636-6.
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.
长-伊文斯肉桂色（LEC）大鼠是一种源自长-伊文斯品系的近交突变大鼠，其特征是由于肝脏铜大量蓄积而出现自发性肝炎。这种蓄积伴随着金属硫蛋白（MT）的显著诱导，据信是由于肝脏向胆管和血管输出铜的内在缺陷所致。在本研究中，研究了四硫代钼酸盐（TTM）对用镉处理的LEC大鼠肝脏铜和镉输出的螯合作用的急性效应。雌性LEC大鼠皮下注射镉（镉；1.0 mg/kg）以诱导镉、铜-金属硫蛋白。费希尔大鼠用镉（镉；1.0 mg/kg）和铜（铜；3.0 mg/kg）处理。注射金属48小时后，在麻醉下静脉注射TTM（5 mg/kg体重）。TTM注射迅速刺激了铜（微克/毫升水平）和镉（纳克/毫升水平）的胆汁排泄。此外，TTM注射后60分钟采集的血清中铜和镉浓度升高。胆汁铜排泄的增加并未伴随着金属硫蛋白胆汁排泄的增加。TTM注射导致LEC大鼠和费希尔大鼠肝脏铜浓度分别从306±2降至262±12微克/克和从43±6降至20±5微克/克。TTM处理未降低肝脏镉浓度。TTM注射也降低了MT组分中肝脏MT和铜的浓度，但未降低镉的浓度。我们的结果表明，TTM可以迅速从MT中去除铜，以增加胆汁和血液中的铜水平。TTM注射刺激的镉输出可能与MT结合铜的去除导致的MT减少有关。我们的结果表明，为避免铜的毒性作用，TTM注射是一种有效的初始治疗方法，尽管包括铜在内的金属最终如何代谢仍有待确定。
