Age-related change in cadmium-induced hepatotoxicity in Wistar rats: role of Kupffer cells and neutrophils.
The hepatotoxicity of cadmium was studied in 1-, 2-, and 6-month-old male Wistar rats. Liver damage, indicated by the increase in serum alanine aminotransferase activity 24 h after sc administration of 3 and 6 mg/kg cadmium, was observed only in 6-month-old rats. Dose-dependent increases in the cadmium content of the liver were similar for all three age groups. Basal and induced metallothionein contents were higher in livers of 1-month-old rats than in those of 2- and 6-month-old rats. In contrast, the basal glutathione content of the liver was higher in 6-month-old rats than in 1- and 2-month-old rats, and glutathione content increased slightly in all three age groups after cadmium administration. Thus, the higher susceptibility to cadmium-induced hepatotoxicity in 6-month-old rats seemed not to be explained by differences in cadmium uptake or by the metallothionein and glutathione contents of the liver. Inactivation of Kupffer cells with gadolinium chloride or depletion of neutrophils with cyclophosphamide relieved cadmium hepatotoxicity only in 6-month-old rats. In addition, 6-month-old rats were more susceptible than 2-month-old rats to lipopolysaccharide-induced hepatotoxicity. The results suggest that age-associated changes in Kupffer cell function and infiltration of neutrophils are important determinants of cadmium-induced hepatotoxicity in rats.
Yamano
T
T
Osaka City Institute of Public Health and Environmental Sciences, 8-34 Tojo-cho, Tennoji-ku, Osaka, 543, Japan.
Shimizu
M
M
Noda
T
T
D000367:Age Factors; D000410:Alanine Transaminase / Q000097:blood; D000477:Alkylating Agents / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D002104:Cadmium / Q000378:metabolism / Q000633:toxicity*; D056486:Chemical and Drug Induced Liver Injury; D003520:Cyclophosphamide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004926:Escherichia coli; D005682:Gadolinium / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D007728:Kupffer Cells / Q000187:drug effects* / Q000473:pathology; D008070:Lipopolysaccharides; D008107:Liver Diseases / Q000378:metabolism / Q000473:pathology; D008297:Male; D008668:Metallothionein / Q000096:biosynthesis; D009504:Neutrophils / Q000187:drug effects* / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar
D000477:Alkylating Agents; D000893:Anti-Inflammatory Agents; D008070:Lipopolysaccharides; D002104:Cadmium; D003520:Cyclophosphamide; D008668:Metallothionein; D005682:Gadolinium; D000410:Alanine Transaminase; D005978:Glutathione; C038958:gadolinium chloride