© 1993 Oxford University Press
research-article |
Induction of Metallothionein by Arsenicals in Mice1
Department of Pharmacology, Toxicology and Therapeutics, Environmental Health and Occupational Medicine Center, University of Kansas Medical Center Kansas City, Kansas 66160-7417
Received June 25, 1992; accepted September 28, 1992
Metallothionein (MT) is a sulfhydryl-rich, metal-binding protein that provides protection against metal toxicity. MT is induced by acute stress, hormones, metals, and various organic compounds. Recently, arsenicals have also been shown to induce MT. However, the mechanism and character of MT induction by arsenicals is unknown. Therefore, the effect of various arsenic forms on the tissue concentration of MT was determined. Mice were injected sc with various doses of arsenite [As(III)], arsenate [As(V)], monomethylarsenate (MMAA), and dimethylarsenate (DMAA), and MT content in the liver was measured 24 hr later by the Cd-hemoglobin radioassay. As(III) is a potent hepatic MT inducer in that a 30-fold increase in MT was observed at the dose of 85 µmol/kg. In comparison, it took 3-, 50-, and 120-fold higher molar amounts of As(V), MMAA, and DMAA, respectively to produce a similar effect. MMAA produces the largest increase in hepatic MT (80-fold), followed by As(III) (30-fold), As(V) (25-fold), and DMAA (10-fold). However, none of the arsenicals induced MT in mouse primary hepatocyte cultures. Both MT-I and MT-II were coordinately induced by As(III), As(V), and MMAA. MT induction by As(III) was further characterized following sc administration of arsenite (85 µmol/kg). Hepatic MT induction peaked at 24 hr, and in addition to the liver, As(III) also increased MT in kidney, spleen, stomach, intestine, heart, and lung. MT-I mRNA increased 24-, 52-, and 11-fold at 3, 6, and 15 hr after As(III) administration. This induction profile is similar to that observed after Zn or Cd exposure. In conclusion, arsenicals are effective inducers of MT in vivo, and their potency and efficacy are dependent on the chemical form of arsenic. As(III) is a potent hepatic MT inducer for both MT-I and MT-II, and this effect is associated with an increase in MT mRNA.