ZINC-INDUCED ARSENITE TOLERANCE IN MICE

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 o f a number of metals. The present studies were designed to examine the role of MT in arsenic toxicity. Zinc (Zn) pretreatment (1000 mu mol/k g, sc) markedly increased hepatic MT (150-fold over controls), and als o protected against the lethal effects of arsenite (130 mu mol/kg, sc) . However, no correlation was found between the ability of various kno wn MT inducers (Zn, Cd, arsenite, monomethylarsenite, alpha-hederin, o r oleanolic acid) to increase hepatic MT and to protect against arseni c 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 injecti on. 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 mic e, as determined by G-75 gel-filtration chromatography. In mice pretre ated with Zn (1000 mu mol/kg, sc) and subsequently injected with arsen ite-73 (115 mu mol/kg, sc), the arsenic-73 content in blood, heart, lu ng, kidneys, spleen, muscle, and skin was lower than in controls, indi cating increased arsenic elimination in Zn-pretreated mice. In conclus ion, Zn pretreatment protects mice against arsenite toxicity, but the mechanism of tolerance does not appear to be induction of MT. (C) 1994 Society of Toxicology.