Transgenic mice that overexpress metallothionein-I are protected from cadmium lethality and hepatotoxicity

Toxicol Appl Pharmacol. 1995 Dec;135(2):222-8. doi: 10.1006/taap.1995.1227.

Abstract

The purpose of this study was to determine whether metallothionein-I (MT-I) transgenic female mice (MT-TG) are resistant to cadmium (Cd) hepatotoxicity. Female MT-TG mice have 10- to 20-fold higher MT concentrations in liver than control mice and are more resistant to Cd-induced lethality than control mice. CdCl2 (3.7 mg Cd/kg, iv) was lethal to 73% of control mice, but only to 13% of MT-TG mice. Cd administration (3.1 mg/kg, iv) to control mice produced extensive liver injury as evidenced by 20- and 70-fold increases in serum enzyme activities of sorbitol dehydrogenase and alanine aminotransferase, respectively. MT-TG mice are considerably more resistant to Cd-induced hepatotoxicity than control mice, as evidenced by only about one-tenth the elevation in serum enzymes observed in control mice and a lower incidence of hepatocyte necrosis in MT-TG mice. To ascertain the mechanism of this protection, the distribution of Cd to various organs and the subcellular distribution of Cd in liver were determined 2 hr after Cd injection (109CdCl2, 3.5 mg Cd/kg, iv). The hepatic subcellular distribution of Cd was altered markedly in MT-TG mice, with much less Cd distributing to nuclei, mitochondria, and microsomes (25, 42, and 24% of controls, respectively), and more Cd to the cytosol (240% of controls). The increased cytosolic Cd was bound primarily to MT, as determined by G-75 gel chromatography. In addition, primary hepatocyte cultures from MT-TG mice maintained higher levels of MT than hepatocytes from control mice and were more resistant to Cd cytotoxicity than control hepatocytes. In conclusion, studies using MT-I transgenic mice demonstrate that MT protects against Cd lethality and hepatotoxicity, and this hepatoprotective effect of MT is also observed in hepatocyte cultures from MT-TG mice.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alanine Transaminase / blood
  • Animals
  • Cadmium / analysis
  • Cadmium / toxicity*
  • Cell Survival / drug effects
  • Cells, Cultured
  • Drug Resistance
  • Female
  • L-Iditol 2-Dehydrogenase / blood
  • Liver / chemistry
  • Liver / cytology
  • Liver / drug effects*
  • Liver / pathology
  • Male
  • Metallothionein / biosynthesis
  • Metallothionein / genetics
  • Metallothionein / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Necrosis / chemically induced
  • Survival Rate

Substances

  • Cadmium
  • Metallothionein
  • L-Iditol 2-Dehydrogenase
  • Alanine Transaminase