Induction of metallothionein by cadmium-metallothionein in rat liver: a proposed mechanism.
Distribution of Cd to various organs following iv administration of CdCl2 (3.5 mg Cd/kg) resulted in more than 43% of total tissue Cd accumulating in the liver. In contrast, after CdMT administration (0.5 mg Cd/kg), only 1% of the Cd was found in liver. Rats administered CdCl2 (1.0 mg Cd/kg) had hepatic MT values 30-fold greater than controls and a hepatic Cd concentration of 17 micrograms/g. In comparison, rats treated with CdMT (0.4 mg Cd/kg) had hepatic MT concentrations 7-fold greater than controls and a hepatic Cd concentration of 0.80 micrograms/g. However, when hepatic MT levels were normalized to tissue Cd concentrations, induction of MT by CdMT was 5-fold greater than by CdCl2. Northern and slot-blot analyses of mRNA showed that both CdCl2 and CdMT coordinately increased MT mRNA. These data suggest that both CdMT and CdCl2 increase hepatic MT by similar mechanisms. A dose-response increase in MT produced by CdCl2 indicated a biphasic response, with low doses producing relatively more hepatic MT than higher doses. In addition, the amount of MT produced per unit Cd after CdMT treatment was similar to those observed after low doses of CdCl2 in the dose-response experiment. These data provide strong evidence to support the conclusion that the apparent potency of CdMT observed here and in previous studies is most likely due to the small amount of Cd distributed to the liver, which is relatively more effective in inducing MT than are higher concentrations.
McKim
J M
JM
Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City 66103.
Liu
J
J
Liu
Y P
YP
Klaassen
C D
CD
D000818:Animals; D001483:Base Sequence; D002104:Cadmium / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D019256:Cadmium Chloride; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008668:Metallothionein / Q000096:biosynthesis* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011919:Rats, Inbred Strains
D012333:RNA, Messenger; C004203:cadmium-binding protein; D002104:Cadmium; D008668:Metallothionein; D019256:Cadmium Chloride