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 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.
Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City 66160.
H
H
Kreppel
J
J
Liu
Y
Y
Liu
F X
FX
Reichl
C D
CD
Klaassen
D000818:Animals; D001151:Arsenic; D018053:Arsenites / Q000037:antagonists & inhibitors* / Q000493:pharmacokinetics / Q000633:toxicity; D008297:Male; D008668:Metallothionein / Q000502:physiology*; D051379:Mice; D008815:Mice, Inbred Strains; D011868:Radioisotopes; D015032:Zinc / Q000494:pharmacology*
D018053:Arsenites; D011868:Radioisotopes; D008668:Metallothionein; D015032:Zinc; C015001:arsenite; D001151:Arsenic