Differential hepatotoxicity induced by cadmium in Fischer 344 and Sprague-Dawley rats.
A number of reports document that Fischer 344 (F344) rats are more susceptible to chemically induced liver injury than Sprague-Dawley (SD) rats. Cadmium (CdCl2), a hepatotoxicant that does not require bioactivation, was used to better define the biological events that are responsible for the differences in liver injury between F344 and SD rats. CdCl2 (3 mg/kg) produced hepatotoxicity in both rat strains, but the hepatic injury was 18-fold greater in F344 rats as assessed by plasma alanine aminotransferase (ALT) activity. This difference in toxicity was not observed when isolated hepatocytes were incubated with CdCl2 in vitro, indicating that other cell types contribute to Cd-induced hepatotoxicity in vivo. Indeed, the sieve plates of hepatic endothelial cells (EC) in F344 rats were damaged to a greater degree than EC in SD rats. Additionally, Kupffer cell (KC) inhibition reduced hepatotoxicity in both strains, suggesting that this cell type is involved in the progression of CdCl2-induced hepatotoxicity. Moreover, enhanced synthesis of heat shock protein 72 occurred earlier in the SD rat. Maximal levels of hepatic metallothionein (MT), a protein associated with cadmium tolerance, were greater in SD rats. These protective factors may limit CdCl2-induced hepatocellular injury in SD compared with F344 rats by reducing KC activation and the subsequent inflammatory response that allows for the progression of hepatic injury.
Kuester
Robert K
RK
Department of Pharmacology and Toxicology, Center for Toxicology, The University of Arizona, P.O. Box 210207, Tucson, Arizona 85721-0207, USA.
Waalkes
Michael P
MP
Goering
Peter L
PL
Fisher
Ben L
BL
McCuskey
Robert S
RS
Sipes
I Glenn
IG
D000410:Alanine Transaminase / Q000097:blood*; D000818:Animals; D019256:Cadmium Chloride / Q000008:administration & dosage; D002105:Cadmium Poisoning / Q000201:enzymology* / Q000401:mortality; D004305:Dose-Response Relationship, Drug; D004727:Endothelium / Q000187:drug effects / Q000473:pathology; D050884:HSP72 Heat-Shock Proteins; D006360:Heat-Shock Proteins / Q000096:biosynthesis; D022781:Hepatocytes / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000473:pathology / Q000648:ultrastructure; D008297:Male; D008668:Metallothionein / Q000096:biosynthesis; D008854:Microscopy, Electron; D008855:Microscopy, Electron, Scanning; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley
D050884:HSP72 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D008668:Metallothionein; D000410:Alanine Transaminase; D019256:Cadmium Chloride