title: Metal ion-mediated regulation of heme oxygenase induction in cultured avian liver cells.
abstract: The induction of heme oxygenase (EC 1.14.99.3) in response to various metal treatments was investigated in monolayer cultures of chick embryo liver cells maintained in a chemically defined serum-free medium. The most potent heme oxygenase-inducing action was exhibited by CO2+, Cd2+, Sb3+, As3+, and Au1+ followed by lesser induction observed with Cu2+, Fe2+, and Fe3+. Mn2+, Ni2+, Se4+, Sn2+, and Zn2+ were without effect. In contrast to the marked inducing effect of Co2+ on heme oxygenase, Co-protoporphyrin IX decreased the enzyme activity in a dose-dependent manner. Addition of Zn2+ (20 microM) to Co2+-treated liver cell cultures revealed a striking ability of Zn2+ to block completely Co2+-induced heme oxygenase. Simultaneous addition of Mn2+ (50 microM) to Co2+-treated cells also blocked Co2+-induced heme oxygenase (approximately 50%). These findings in tissue culture confirm those made earlier in whole animals (Drummond, G. S., and Kappas, A. (1979) Proc. Natl. Acad. Sci. U. S. A. 76, 5331-5335) and indicate that these effects of Zn2+ and Mn2+ are exerted directly in liver cells. Addition of cysteine (400 microM) to the cultures also inhibited heme oxygenase induction by Co2+ substantially. Cycloheximide and actinomycin D blocked the induction of heme oxygenase, indicating that increased heme oxygenase activity by metal treatment is dependent on fresh RNA and protein synthesis. The half-life of the enzyme was calculated to be approximately 15 h after treatment with cycloheximide. These findings provide further evidence that metal ions can regulate heme oxygenase synthesis directly in isolated liver cells and that the metal-metal interactions which lead to blockade of the enzyme induction do not involve extrahepatic tissues.
mesh_terms: D000818:Animals; D000965:Antimony / Q000494:pharmacology; D001151:Arsenic / Q000494:pharmacology; D002104:Cadmium / Q000494:pharmacology; D002478:Cells, Cultured; D002642:Chick Embryo; D003035:Cobalt / Q000494:pharmacology; D003300:Copper / Q000494:pharmacology; D004790:Enzyme Induction; D006046:Gold / Q000494:pharmacology; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis*; D007501:Iron / Q000494:pharmacology; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008345:Manganese / Q000494:pharmacology; D008670:Metals / Q000494:pharmacology*; D006899:Mixed Function Oxygenases / Q000096:biosynthesis*; D015032:Zinc / Q000494:pharmacology
chemical_list: D008670:Metals; D002104:Cadmium; D003035:Cobalt; D008345:Manganese; D006046:Gold; D003300:Copper; D000965:Antimony; D007501:Iron; D006899:Mixed Function Oxygenases; D006419:Heme Oxygenase (Decyclizing); D015032:Zinc; D001151:Arsenic