Liu J, Choudhuri S, Liu Y, Kreppel H, Andrews G K, Klaassen C D
Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City 66160-7417.
Toxicol Appl Pharmacol. 1993 Jul;121(1):144-51. doi: 10.1006/taap.1993.1139.
alpha-Hederin (alpha-Hed) is a triterpenoid saponin that has been shown to protect against some hepatotoxicants. This study examined the protective effect of alpha-Hed against cadmium (Cd) hepatotoxicity and the mechanism of protection. alpha-Hed pretreatment (100 mumol/kg, sc) dramatically decreased Cd (3.7 mg/kg, iv) hepatotoxicity as indicated by a reduction of serum alanine aminotransferase and sorbitol dehydrogenase, as well as by histopathological examination. alpha-Hed did not produce protection by decreasing the distribution of Cd to the liver, as higher amounts of Cd were found in the liver of alpha-Hed-pretreated mice. However, there was a marked alteration in subcellular distribution of Cd in the alpha-Hed-pretreated mice, with much less Cd distributing to nuclei, mitochondria, and microsomes and more in the cytosol. The increased cytosolic Cd was found primarily bound to a low-molecular-weight protein, metallothionein (MT). alpha-Hed (10-300 mumol/kg, sc) produced a dose-dependent increase in hepatic MT with a 100-fold increase over controls 24 hr after a single injection of 100 mumol/kg, as determined by the Cd/hemoglobin assay. The hepatic MT increase produced by alpha-Hed is relatively long lasting, in that it is still eight times control values 6 days after a single administration. The induction of MT was also relatively specific for the liver, as little or no increase in MT was observed in other tissues. Furthermore, alpha-Hed increased both hepatic MT-I and MT-II levels. Northern blot analysis revealed that alpha-Hed rapidly increased MT mRNA levels. In conclusion, alpha-Hed decreases the hepatotoxicity of Cd by inducing MT, which binds Cd in the cytosol, and thus reduces the amount of Cd in the critical cellular organelles. alpha-Hed is an effective inducer of both MT-I and MT-II in liver, and this effect is associated with an increase in MT mRNA.
α-常春藤皂苷（α-Hed）是一种三萜皂苷，已被证明可抵御某些肝毒性物质。本研究考察了α-Hed对镉（Cd）肝毒性的保护作用及其保护机制。α-Hed预处理（100 μmol/kg，皮下注射）显著降低了Cd（3.7 mg/kg，静脉注射）的肝毒性，血清丙氨酸转氨酶和山梨醇脱氢酶降低以及组织病理学检查结果均表明了这一点。α-Hed并非通过减少Cd在肝脏中的分布来产生保护作用，因为在α-Hed预处理小鼠的肝脏中发现了更高含量的Cd。然而，在α-Hed预处理小鼠中，Cd的亚细胞分布有明显改变，分布到细胞核、线粒体和微粒体中的Cd少得多，而在细胞质中更多。发现增加的细胞质Cd主要与一种低分子量蛋白质金属硫蛋白（MT）结合。通过Cd/血红蛋白测定法确定，α-Hed（10 - 300 μmol/kg，皮下注射）可使肝脏MT呈剂量依赖性增加，单次注射100 μmol/kg后24小时，其含量比对照组增加了100倍。α-Hed引起的肝脏MT增加持续时间相对较长，单次给药6天后仍为对照值的8倍。MT的诱导对肝脏也相对具有特异性，因为在其他组织中未观察到MT有少量增加或没有增加。此外，α-Hed增加了肝脏MT-I和MT-II的水平。Northern印迹分析显示，α-Hed迅速增加了MT mRNA水平。总之，α-Hed通过诱导MT降低Cd的肝毒性，MT在细胞质中结合Cd，从而减少关键细胞器中的Cd含量。α-Hed是肝脏中MT-I和MT-II的有效诱导剂，这种作用与MT mRNA的增加有关。
