title: Suppression of Kupffer cell function prevents cadmium induced hepatocellular necrosis in the male Sprague-Dawley rat.
abstract: Exposure of humans to toxic metals and metalloids is a major environmental problem. Many metals, such as cadmium, can be hepatotoxic. However, the mechanisms by which metals cause acute hepatic injury are in many cases unknown. Previous reports suggest a major role for inflammation in acute cadmium induced hepatotoxicity. In initial experiments we found that a non-hepatotoxic dose of cadmium chloride (CdCl2; 2.0 mg/kg, i.v.) markedly increased the clearance rate of colloidal carbon from the blood, which is indicative of enhanced phagocytic activity by Kupffer cells (resident hepatic macrophages). Thus. the objective these studies was to determine the involvement of Kupffer cells in cadmium induced liver injury by inhibiting their function with gadolinium chloride (GdCl3). Male Sprague-Dawley rats were administered GdCl3 (10 mg/kg, i.v.) followed 24 h later by a single dose of CdCl2 (3.0 and 4.0 mg/kg, i.v.). Twenty four hours after CdCl2 administration animals were killed and the degree of liver toxicity was assessed using plasma alanine aminotransferase (ALT), as well as light microscopy. Cadmium chloride administration produced multifocal hepatocellular necrosis and increased plasma ALT activity. Pretreatment with GdCl3 significantly reduced both the morphological changes and hepatic ALT release caused by CdCl2. However, the protection was specific to the liver, and did not alter CdCl2 induced testicular injury, as determined by histopathological damage. In many cases, the inducible cadmium-binding protein, metallothionein (MT) is often an essential aspect of the acquisition of cadmium tolerance in the liver. Although cadmium caused a dramatic induction of hepatic MT (32-fold), GdCl3 caused only a minor increase (2-fold). Combined CdCl2 and GdCl3 treatment did not induce levels to an extent greater than CdCl2 alone. As expected, GdCl3 also caused a slight increase in the amount of cadmium associated with the liver. In cultured hepatocytes isolated from GdCl3 pretreated rats, CdCl2 induced cytotoxicity was not significantly altered compared to control hepatocytes, indicating that the mechanism of tolerance required the presence of other cell types. Thus, GdCl3 attenuation of CdCl2 induced hepatotoxicity does not appear to be caused by increased tissue MT content or a decreased susceptibility of hepatocytes to cadmium. From these data, we concluded that tolerance to cadmium induced hepatotoxicity involves the inhibition of Kupffer cell function which results in a decreased inflammatory response and an altered progression of hepatic injury. These data further indicate that Kupffer cell function is critical to cadmium induced hepatocellular necrosis.
authors.affiliation: Department of Pharmacology and Toxicology, Center for Toxicology, The University of Arizona, Tucson 85721-0207, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Sauer
authors.forename: M P
authors.initials: MP
authors.lastname: Waalkes
authors.forename: S B
authors.initials: SB
authors.lastname: Hooser
authors.forename: R K
authors.initials: RK
authors.lastname: Kuester
authors.forename: C A
authors.initials: CA
authors.lastname: McQueen
authors.forename: I G
authors.initials: IG
authors.lastname: Sipes
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D019256:Cadmium Chloride / Q000008:administration & dosage / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity*; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005682:Gadolinium / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D006074:Gout Suppressants / Q000008:administration & dosage / Q000494:pharmacology*; D007275:Injections, Intravenous; D007728:Kupffer Cells / Q000166:cytology / Q000187:drug effects* / Q000473:pathology; D007928:Lethal Dose 50; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000473:pathology; D008107:Liver Diseases / Q000473:pathology / Q000517:prevention & control; D008297:Male; D008668:Metallothionein / Q000378:metabolism; D009336:Necrosis; D010587:Phagocytosis / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013737:Testis / Q000187:drug effects / Q000473:pathology; D014018:Tissue Distribution
chemical_list: D002273:Carcinogens; D006074:Gout Suppressants; D008668:Metallothionein; D005682:Gadolinium; D000410:Alanine Transaminase; D019256:Cadmium Chloride; C038958:gadolinium chloride