Kreppel H, Liu J, Liu Y, Reichl F X, Klaassen C D
Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City 66160.
Fundam Appl Toxicol. 1994 Jul;23(1):32-7. doi: 10.1006/faat.1994.1075.
The mechanism of tolerance to arsenic toxicity is not known. Recently it has been shown that arsenic induces metallothionein (MT), which is a sulfhydryl-rich, metal-binding protein that decreases the toxicity of a number of metals. The present studies were designed to examine the role of MT in arsenic toxicity. Zinc (Zn) pretreatment (1000 mumol/kg, sc) markedly increased hepatic MT (150-fold over controls), and also protected against the lethal effects of arsenite (130 mumol/kg, sc). However, no correlation was found between the ability of various known MT inducers (Zn, Cd, arsenite, monomethylarsenite, alpha-hederin, or oleanolic acid) to increase hepatic MT and to protect against arsenic lethality in mice. To examine the mechanism of Zn protection against arsenic toxicity, the subcellular distribution of arsenite in liver, kidney, and small intestine was determined 2 hr after arsenite injection. Zn pretreatment did not markedly alter the amount of arsenic-73 in the cytosol or the various cellular organelles (nuclei, mitochondria, microsomes) in liver kidney, or small intestine. There was also very little arsenic-73 bound to MT in the cytosol of the Zn-pretreated mice, as determined by G-75 gel-filtration chromatography. In mice pretreated with Zn (1000 mumol/kg, sc) and subsequently injected with arsenite-73 (115 mumol/kg, sc), the arsenic-73 content in blood, heart, lung, kidneys, spleen, muscle, and skin was lower than in controls, indicating increased arsenic elimination in Zn-pretreated mice. In conclusion, Zn pretreatment protects mice against arsenite toxicity, but the mechanism of tolerance does not appear to be induction of MT.
对砷毒性产生耐受性的机制尚不清楚。最近有研究表明，砷可诱导金属硫蛋白（MT）的产生，MT是一种富含巯基的金属结合蛋白，可降低多种金属的毒性。本研究旨在探讨MT在砷毒性中的作用。锌（Zn）预处理（1000 μmol/kg，皮下注射）可显著增加肝脏MT（比对照组高150倍），并能预防亚砷酸盐（130 μmol/kg，皮下注射）的致死作用。然而，在各种已知的MT诱导剂（锌、镉、亚砷酸盐、一甲基亚砷酸盐、α-常春藤皂苷或齐墩果酸）增加肝脏MT的能力与保护小鼠免受砷致死性之间，未发现相关性。为了研究锌对砷毒性的保护机制，在注射亚砷酸盐2小时后，测定了肝脏、肾脏和小肠中亚砷酸盐的亚细胞分布。锌预处理并未显著改变肝脏、肾脏或小肠细胞质或各种细胞器（细胞核、线粒体、微粒体）中砷-73的含量。通过G-75凝胶过滤色谱法测定，在锌预处理小鼠的细胞质中，与MT结合的砷-73也很少。在用锌（1000 μmol/kg，皮下注射）预处理并随后注射砷-73（115 μmol/kg，皮下注射）的小鼠中，血液、心脏、肺、肾脏、脾脏、肌肉和皮肤中的砷-73含量低于对照组，表明锌预处理小鼠的砷排泄增加。总之，锌预处理可保护小鼠免受亚砷酸盐毒性，但耐受机制似乎不是诱导MT。
