TRANSGENIC MICE THAT OVEREXPRESS METALLOTHIONEIN-I ARE PROTECTED FROMCADMIUM LETHALITY AND HEPATOTOXICITY

The purpose of this study was to determine whether metallothionein-I ( MT-I) transgenic female mice (MT-TG) are resistant to cadmium (Cd) hep atotoxicity. Female MT-TG mice have 10- tb 20-fold higher MT concentra tions 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 evide nced by 20- and 70-fold increases in serum enzyme activities of sorbit ol dehydrogenase and alanine aminotransferase, respectively. MT-TG mic e are considerably more resistant to Cd-induced hepatotoxicity than co ntrol mice, as evidenced by only about one-tenth the elevation in seru m 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 distrib ution of Cd in liver were determined 2 hr after Cd injection ((109)CdC L(2), 3.5 mg Cd/kg, iv). The hepatic subcellular distribution of Cd wa s altered markedly in MT-TG mice, with much less Cd distributing to nu clei, mitochondria, and microsomes (25, 42, and 24% of controls, respe ctively), and more Cd to the cytosol (240% of controls). The increased cytosolic Cd was bound primarily to MT, as determined by G-75 gel chr omatography. 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 co nclusion, studies using MT-I transgenic mice demonstrate that MT prote cts against Cd lethality and hepatotoxicity, and this hepatoprotective effect of MT is also observed in hepatocyte cultures from MT-TG mice. (C) 1995 Academic Press, Inc.