title: iNOS-null mice are not resistant to cadmium chloride-induced hepatotoxicity.
abstract: Acute administration of cadmium (Cd) to rats results in hepatotoxicity. Recent reports indicate that Kupffer cells, the resident macrophages of the liver, participate in the manifestation of Cd-induced hepatotoxicity. Nitric oxide (NO) is a reactive nitrogen radical produced by activated Kupffer cells via the induction of inducible nitric oxide synthase (iNOS). Nitric oxide can combine with superoxide to form peroxynitrite, a molecule that may participate in the toxic mechanisms of hepatotoxins, such as acetaminophen and bacterial endotoxin. It has been speculated that Cd also may exert its hepatotoxicity, in part, via the production of NO by iNOS. Therefore, this study was undertaken to determine whether iNOS contributes to Cd-induced hepatotoxicity. Wild-type (WT) mice were administered selective iNOS inhibitors (AMT and 1400W) concurrently and 3 h after administration of a hepatotoxic dose of Cd (4.0 mg Cd/mg). Additionally, WT and iNOS-null (iNOS-KO) mice were dosed iv with saline or 2.0, 2.5, 3.0, 3.5 or 4.0 mg Cd/kg. Serum alanine aminotransferase (ALT) and sorbitol dehydrogenase (SDH) activities were quantified to assess liver injury. Administration of iNOS inhibitors failed to prevent Cd-induced hepatotoxicity. Also, Cd caused a dose-dependent increase in liver injury in both WT and iNOS-KO mice. The liver injury produced by Cd in the iNOS-KO mice was not different from that in WT at any dose. These data indicate that iNOS does not appear to mediate Cd-induced hepatotoxicity.
authors.affiliation: Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160-7417, USA.
authors.forename: Eric B
authors.initials: EB
authors.lastname: Harstad
authors.forename: Curtis D
authors.initials: CD
authors.lastname: Klaassen
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000578:Amidines / Q000494:pharmacology; D000818:Animals; D001596:Benzylamines / Q000494:pharmacology; D019256:Cadmium Chloride / Q000378:metabolism / Q000633:toxicity*; D056486:Chemical and Drug Induced Liver Injury; D004791:Enzyme Inhibitors; D005260:Female; D006651:Histocytochemistry; D007064:L-Iditol 2-Dehydrogenase / Q000097:blood; D008107:Liver Diseases / Q000201:enzymology* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D013843:Thiazines / Q000494:pharmacology
chemical_list: C093124:2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine; D000578:Amidines; D001596:Benzylamines; D004791:Enzyme Inhibitors; C104820:N-(3-(aminomethyl)benzyl)acetamidine; D013843:Thiazines; D009569:Nitric Oxide; D007064:L-Iditol 2-Dehydrogenase; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D000410:Alanine Transaminase; D019256:Cadmium Chloride