Strain difference of cadmium accumulation by liver slices of inbred Wistar-Imamichi and Fischer 344 rats.

Strain difference in the accumulation of cadmium (Cd) by liver slices was examined in inbred Cd-resistant Wistar-Imamichi (WI) and Cd-sensitive Fischer 344 (F344) rats. The accumulation of Cd by liver slices of WI rats was significantly lower than that of F344 rats, suggesting strain-related differences in the transport of Cd into the liver cells of these two rat strains. In addition, a similar strain difference was observed in the accumulation of zinc (Zn) by liver slices from WI and F344 rats. Cd accumulation by F344 liver slices decreased when Zn was added to the medium in combination with Cd. Furthermore, in F344 liver slices, Zn accumulation was significantly decreased when Cd was added to the medium. These results suggest that the accumulation of Cd by the liver is probably mediated, at least in part, by Zn transport systems. However, we found no strain difference in hepatic ZnT3 or ZIP3 transcript levels between WI and F344 rats. Further work is in progress to identify the transporter that causes the strain differences in hepatic Cd accumulation seen with WI and F344 rats.

A possible mechanism of resistance to cadmium toxicity in male Long-Evans rats.

The susceptibility to cadmium (Cd)-induced toxicity in male Long-Evans (LE) rats was compared with that in male Fischer 344 (Fischer) and Wistar-Imamichi (WI) rats, which are sensitive and resistant, respectively, to Cd toxicity. All rats of the LE and WI strains survived for 7 days after the treatment with a toxic dose of Cd (6.5mg/kg b.w.). However, all rats of the Fischer strain died by the following day. The strong resistance to Cd toxicity in the LE strain was confirmed to be independent of metallothionein synthesis induced by Cd. The hepatic and renal Cd contents after its administration were significantly lower in the LE strain than in the Fischer strain. Furthermore, the hepatic and renal zinc (Zn) contents after its administration were significantly lower in the LE strain than in the Fischer strain. These limited data suggest that the strong resistance to Cd toxicity in male LE rats results from, at least in part, the lower accumulation of the metal in the liver and kidney, in a similar mechanism as the lower Zn accumulation.

Strain differences of cadmium-induced hepatotoxicity in Wistar-Imamichi and Fischer 344 rats: involvement of cadmium accumulation.

We previously reported that Wistar-Imamichi (WI) rats have a strong resistance to cadmium (Cd)-induced lethality compared to other strains such as Fischer 344 (Fischer) rats. The present study was designed to establish biochemical and histological differences in Cd toxicity in WI and Fischer rats, and to clarify the mechanistic basis of these strain differences. A single Cd (4.5 mg/kg, s.c.) treatment caused a significant increase in serum alanine aminotransferase activity, indicative of hepatotoxicity, in Fischer rats, but did not in WI rats. This difference in hepatotoxic response to Cd was supported by pathological analysis. After treatment with Cd at doses of 3.0, 3.5 and 4.5 mg/kg, the hepatic and renal accumulation of Cd was significantly lower in the WI rats than in the Fischer rats, indicating a kinetic mechanism for the observed strain differences in Cd toxicity. Thus, the remarkable resistance to Cd-induced hepatotoxicity in WI rats is associated, at least in part, with a lower tissue accumulation of the metal. Hepatic and renal zinc (Zn) contents after administration were similarly lower in WI than in Fischer rats. When Zn was administered in combination with Cd to Fischer rats, it decreased Cd contents in the liver and kidney, and exhibited a significant protective effect against the toxicity of Cd. We propose the possibility that Zn transporter plays an important role in the strain difference of Cd toxicity in WI and Fischer rats.