Liu Y, Liu J, Iszard M B, Andrews G K, Palmiter R D, Klaassen C D
Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City 66160-7417, USA.
Toxicol Appl Pharmacol. 1995 Dec;135(2):222-8. doi: 10.1006/taap.1995.1227.
The purpose of this study was to determine whether metallothionein-I (MT-I) transgenic female mice (MT-TG) are resistant to cadmium (Cd) hepatotoxicity. Female MT-TG mice have 10- to 20-fold higher MT concentrations in liver than control mice and are more resistant to Cd-induced lethality than control mice. CdCl2 (3.7 mg Cd/kg, iv) was lethal to 73% of control mice, but only to 13% of MT-TG mice. Cd administration (3.1 mg/kg, iv) to control mice produced extensive liver injury as evidenced by 20- and 70-fold increases in serum enzyme activities of sorbitol dehydrogenase and alanine aminotransferase, respectively. MT-TG mice are considerably more resistant to Cd-induced hepatotoxicity than control mice, as evidenced by only about one-tenth the elevation in serum enzymes observed in control mice and a lower incidence of hepatocyte necrosis in MT-TG mice. To ascertain the mechanism of this protection, the distribution of Cd to various organs and the subcellular distribution of Cd in liver were determined 2 hr after Cd injection (109CdCl2, 3.5 mg Cd/kg, iv). The hepatic subcellular distribution of Cd was altered markedly in MT-TG mice, with much less Cd distributing to nuclei, mitochondria, and microsomes (25, 42, and 24% of controls, respectively), and more Cd to the cytosol (240% of controls). The increased cytosolic Cd was bound primarily to MT, as determined by G-75 gel chromatography. In addition, primary hepatocyte cultures from MT-TG mice maintained higher levels of MT than hepatocytes from control mice and were more resistant to Cd cytotoxicity than control hepatocytes. In conclusion, studies using MT-I transgenic mice demonstrate that MT protects against Cd lethality and hepatotoxicity, and this hepatoprotective effect of MT is also observed in hepatocyte cultures from MT-TG mice.
本研究的目的是确定金属硫蛋白-I（MT-I）转基因雌性小鼠（MT-TG）是否对镉（Cd）肝毒性具有抗性。雌性MT-TG小鼠肝脏中的MT浓度比对照小鼠高10至20倍，并且比对照小鼠更能抵抗Cd诱导的致死性。CdCl2（3.7 mg Cd/kg，静脉注射）对73%的对照小鼠具有致死性，但对仅13%的MT-TG小鼠具有致死性。给对照小鼠静脉注射Cd（3.1 mg/kg）会导致广泛的肝损伤，这分别由山梨醇脱氢酶和丙氨酸氨基转移酶的血清酶活性增加20倍和70倍所证实。MT-TG小鼠比对照小鼠对Cd诱导的肝毒性具有更强的抗性，这表现为MT-TG小鼠血清酶升高幅度仅为对照小鼠的约十分之一，且肝细胞坏死发生率更低。为了确定这种保护机制，在注射Cd（109CdCl2，3.5 mg Cd/kg，静脉注射）2小时后，测定了Cd在各个器官中的分布以及肝脏中Cd的亚细胞分布。MT-TG小鼠肝脏中Cd的亚细胞分布发生了明显改变，分布到细胞核、线粒体和微粒体中的Cd显著减少（分别为对照的25%、42%和24%），而分布到胞质溶胶中的Cd增多（为对照的240%）。通过G-75凝胶色谱法测定，胞质溶胶中增加的Cd主要与MT结合。此外，来自MT-TG小鼠的原代肝细胞培养物中MT水平高于对照小鼠的肝细胞，并且比对照肝细胞更能抵抗Cd细胞毒性。总之，使用MT-I转基因小鼠的研究表明，MT可预防Cd致死性和肝毒性，并且在来自MT-TG小鼠的肝细胞培养物中也观察到了MT的这种肝保护作用。
