Klaassen C D, Liu J
Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City 66160-7417, USA.
Environ Health Perspect. 1998 Feb;106 Suppl 1(Suppl 1):297-300. doi: 10.1289/ehp.98106s1297.
Pretreatment of rats with low doses of Cd produces adaptive tolerance to a subsequent high dose of Cd-induced lethality, thus shifting the dose-response curve to the right. Cd pretreatment of animals also protects against the hepatotoxicity produced by high doses of Cd. This protection is attributable to the 10- to 50-fold induction of hepatic metallothionein (MT) by Cd pretreatment. As a result hepatic subcellular distribution of Cd is significantly altered, with more Cd bound to MT in the cytosol and a concomitant reduction of Cd in other critical organelles. In addition MT-transgenic animals are more resistant, whereas MT-null mice are more sensitive than controls to Cd-induced lethality and hepatotoxicity. This further demonstrates that MT is important in Cd detoxication. Induction of hepatic MT by zinc also protects mice from carbon tetrachloride (CCl4)-induced liver injury, with more 14C-CCl4 bound to MT in the cytosol. MT-null mice are more sensitive to CCl4-induced hepatotoxicity, which supports the hypothesis that induction of MT also plays a protective role for nonmetallic chemicals. These results indicate that MT is a part of cellular adaptive mechanisms affecting the magnitude and progression of toxic insults from metals such as Cd as well as from organic chemicals such as CCl4.
用低剂量镉对大鼠进行预处理可使其对随后高剂量镉诱导的致死作用产生适应性耐受，从而使剂量反应曲线右移。对动物进行镉预处理还可防止高剂量镉产生的肝毒性。这种保护作用归因于镉预处理使肝脏金属硫蛋白（MT）诱导增加10至50倍。结果，镉在肝脏亚细胞中的分布发生显著改变，更多的镉与胞质溶胶中的MT结合，同时其他关键细胞器中的镉含量减少。此外，MT转基因动物更具抗性，而MT基因敲除小鼠对镉诱导的致死作用和肝毒性比对照更敏感。这进一步证明MT在镉解毒中很重要。锌诱导肝脏MT也可保护小鼠免受四氯化碳（CCl4）诱导的肝损伤，更多的14C-CCl4与胞质溶胶中的MT结合。MT基因敲除小鼠对CCl4诱导的肝毒性更敏感，这支持了MT诱导对非金属化学物质也起保护作用的假说。这些结果表明，MT是细胞适应性机制的一部分，影响来自镉等金属以及CCl4等有机化学物质的毒性损伤的程度和进程。
