Tumor necrosis factor-alpha-null mice are not resistant to cadmium chloride-induced hepatotoxicity.
Acute administration of cadmium results in hepatotoxicity. Recent reports indicate that Kupffer cells, the resident macrophages of the liver, participate in the manifestation of chemical-induced hepatotoxicity. Tumor necrosis factor-alpha (TNF-alpha) is a proinflammatory cytokine that is a major product of Kupffer cells and mediates the hepatotoxic effects of lipopolysaccharide (LPS). It has been speculated that cadmium also may exert its hepatotoxicity via the production of TNF-alpha by the Kupffer cells. Therefore, this study was undertaken to determine whether mice deficient in TNF-alpha are resistant to Cd-induced hepatotoxicity. TNF-alpha-null (TNF-KO) and wild-type (WT) mice were dosed ip with saline, LPS (0.1 mg/kg)/Gln (d-galactosamine, 700 mg/kg), or CdCl2 (2.2, 2.8, 3.4, and 3.9 mg Cd/kg). Serum alanine aminotransferase (ALT) and sorbitol dehydrogenase (SDH) activities were quantified to assess liver injury. Caspase-3 activity was quantified to assess hepatocellular apoptosis. LPS/Gln treatment increased ALT (17-fold) and SDH (21-fold) in WT mice. In contrast, LPS/Gln-treatment did not significantly increase ALT or SDH in TNF-KO mice. LPS/Gln-treatment caused a 7.8-fold increase in caspase-3 activity in WT mice but did not increase caspase-3 in TNF-KO mice. Cadmium caused a dose-dependent increase in liver injury in both WT and TNF-KO mice. However, the liver injury produced by Cd in the TNF-KO mice was not different from that in WT at any dose. No significant increase in caspase-3 activity was detected in any of the Cd-treated mice. These data indicate that, in contrast to LPS/Gln-induced hepatotoxicity, TNF-alpha does not appear to mediate Cd-induced hepatotoxicity.
Harstad
Eric B
EB
Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160, USA.
Klaassen
Curtis D
CD
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D019256:Cadmium Chloride / Q000633:toxicity*; D053148:Caspase 3; D020169:Caspases / Q000032:analysis; D056486:Chemical and Drug Induced Liver Injury; D005688:Galactosamine / Q000494:pharmacology; D006651:Histocytochemistry; D007064:L-Iditol 2-Dehydrogenase / Q000097:blood; D008070:Lipopolysaccharides / Q000494:pharmacology; D008107:Liver Diseases / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency / Q000502:physiology*
D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D005688:Galactosamine; D007064:L-Iditol 2-Dehydrogenase; D000410:Alanine Transaminase; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D019256:Cadmium Chloride