Transgenic mice that overexpress metallothionein-I are protected from cadmium 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) 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.
Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City 66160-7417, USA.
Y
Y
Liu
J
J
Liu
M B
MB
Iszard
G K
GK
Andrews
R D
RD
Palmiter
C D
CD
Klaassen
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D002104:Cadmium / Q000032:analysis / Q000633:toxicity*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004351:Drug Resistance; D005260:Female; D007064:L-Iditol 2-Dehydrogenase / Q000097:blood; D008099:Liver / Q000737:chemistry / Q000166:cytology / Q000187:drug effects* / Q000473:pathology; D008297:Male; D008668:Metallothionein / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009336:Necrosis / Q000139:chemically induced; D015996:Survival Rate
D002104:Cadmium; D008668:Metallothionein; D007064:L-Iditol 2-Dehydrogenase; D000410:Alanine Transaminase