title: Effects of hemin on rat liver cyclic AMP-dependent protein kinases in cell extracts and intact hepatocytes.
abstract: Cyclic AMP-dependent protein kinases I and II, partially purified from rat liver cytosol, were inhibited 50% by 40 microM hemin and 100 microM hemin, respectively. With the purified catalytic subunit of cyclic AMP-dependent protein kinase, hemin caused non-competitive inhibition with respect to the peptide substrate and mixed inhibition with respect to ATP. Hemin also inhibited purified phosphorylase b kinase, indicating that hemin concentrations above 10 microM markedly inhibit multiple protein kinases. In isolated intact hepatocytes, hemin inhibited the glucagon-dependent activation of cyclic AMP-dependent protein kinases and the activation of glycogen phosphorylase. For both effects, high heme concentrations (40-60 microM) were required for 50% inhibition. Similar high levels of exogenous hemin inhibited total hepatocyte protein synthesis. By contrast, 5 microM hemin or less was sufficient to raise intracellular heme levels, as indicated by the relative heme-saturation of tryptophan oxygenase in hepatocytes. Hemin, 5 microM, completely repressed induction of 5-aminolevulinate synthase by dexamethasone in hepatocyte primary cultures. Such repression is unlikely to be mediated by inhibition of protein kinases.
mesh_terms: D000624:5-Aminolevulinate Synthetase / Q000037:antagonists & inhibitors; D000818:Animals; D002474:Cell-Free System; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects; D006418:Heme / Q000031:analogs & derivatives*; D006427:Hemin / Q000494:pharmacology*; D008099:Liver / Q000201:enzymology*; D008297:Male; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000378:metabolism*; D051381:Rats
chemical_list: D047428:Protein Kinase Inhibitors; D006418:Heme; D006427:Hemin; D000242:Cyclic AMP; D000624:5-Aminolevulinate Synthetase; D011494:Protein Kinases