The involvement of Kupffer cells in carbon tetrachloride toxicity.
Carbon tetrachloride (CCl4) is a classical pericentral hepatotoxicant; however, precise details of its mechanism of action remain unknown. One possibility is that Kupffer cells participant in this mechanism since CCl4 elevates calcium, and the release of toxic eicosanoids and cytokines by Kupffer cells is calcium-dependent. Therefore, these studies were designed to evaluate the role of Kupffer cells in CCl4 toxicity in the rat in vivo. Kupffer cells were destroyed selectively with gadolinium chloride treatment (10 mg/kg GdCl3 iv) 1 day prior to administration of CCl4 (4 g/kg ig). Twenty-four hours after CCl4 treatment, rats were anesthetized, blood samples were drawn for aspartate aminotransferase (AST) determination, which is indicative of parenchymal cell damage, and trypan blue was infused into the liver to stain the nuclei of dead hepatocytes. AST levels were in the normal range and trypan blue staining was negligible in livers from vehicle- or GdCl3-treated rats. As expected, CCl4 treatment alone elevated AST levels to values over 4000 U/liter and caused massive cell death (60-90 trypan blue-positive cells/pericentral field). In dramatic contrast, the elevation in AST and cell death due to CCl4 were almost completely prevented by GdCl3 treatment. In attempts to understand this phenomenon, metabolic and detoxification pathways were assessed. CCl4 is metabolized via cytochrome P450 II.E.1; however, GdCl3 treatment did not alter this pathway as assessed from p-nitrocatechol formation from the selective substrate, p-nitrophenol. GdCl3 treatment also had no effect on hepatic glutathione levels. On the other hand, GdCl3 treatment significantly reduced infiltration of neutrophils resulting from exposure to CCl4. These data clearly support the hypothesis that Kupffer cells participate in the mechanism of toxicity of CCl4 in vivo, possibly by release of chemoattractants for neutrophils.
Edwards
M J
MJ
Department of Pharmacology, University of North Carolina, Chapel Hill 27599-7365.
Keller
B J
BJ
Kauffman
F C
FC
Thurman
R G
RG
D000818:Animals; D001219:Aspartate Aminotransferases / Q000187:drug effects; D002251:Carbon Tetrachloride / Q000633:toxicity*; D002396:Catechols / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D005260:Female; D005682:Gadolinium / Q000494:pharmacology; D007728:Kupffer Cells / Q000187:drug effects* / Q000502:physiology; D008099:Liver / Q000187:drug effects; D009596:Nitrophenols / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016028:Receptors, Leukocyte-Adhesion / Q000187:drug effects
D002396:Catechols; D009596:Nitrophenols; D016028:Receptors, Leukocyte-Adhesion; D005682:Gadolinium; D002251:Carbon Tetrachloride; D001219:Aspartate Aminotransferases; C038958:gadolinium chloride; C001833:4-nitrocatechol; C024836:4-nitrophenol