Cobalt regulation of heme synthesis and degradation in avian embryo liver cell culture.
Inorganic cobalt was found to induce heme oxygenase activity in primary cultures of embryonic chick liver cells and to inhibit the induction of delta-aminolevulinate synthetase by the porphyrinogenic compounds allylisopropylacetamide, dicarbethoxy-1,4-dihydrocollidine, etiocholanolone, phenobarbital, Aroclor (R)1254, and secobarbital. Much smaller concentrations of Co2+ (5 muM) were required to inhibit delta-aminolevulinate synthetase than to induce heme oxygenase activity (50 muM). These effects of Co2+ on heme synthesis and heme degradation were potentiated by depletion of cellular glutathione content as a result of treatment with diethyl maleate. Cobalt inhibition of the induction of delta-aminolevulinate synthetase was of the same magnitude and probably involved the same mechanism as that produced by cobalt heme dimethyl ester and iron heme. The induction of heme oxygenase by cobalt could be blocked by cycloheximide. Plasma protein synthesis was not inhibited in the presence of concentrations of Co2+ which produced inhibition of delta-aminolevulinate synthetase or induction of heme oxygenase. Other metals such as Cd2+ and Cu2+ also inhibited the induction of delta-aminolevulinate synthetase by allylisopropylacetamide. These findings indicate that Co2+ can regulate heme metabolism directly in liver cells without intermediate actions on extrahepatic tissues. It is suggested that regulation of production of delta-aminolevulinate synthetase and heme oxygenase is mediated through the action of the metal ion rather than the metal in the form of a tetrapyrrole chelate.
D000818:Animals; D002413:Cations, Divalent; D002478:Cells, Cultured; D002642:Chick Embryo; D003035:Cobalt / Q000494:pharmacology*; D003513:Cycloheximide / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D006418:Heme / Q000096:biosynthesis / Q000378:metabolism*; D007501:Iron / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008298:Maleates / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000378:metabolism
D002413:Cations, Divalent; D008298:Maleates; D003609:Dactinomycin; D003035:Cobalt; D006418:Heme; D003513:Cycloheximide; D007501:Iron; D006899:Mixed Function Oxygenases