Hepatic 5-aminolevulinic acid synthase mRNA stability is modulated by inhibitors of heme biosynthesis and by metalloporphyrins
AuthorsCable, Edward Earl
Gildemeister, Otto S.
Pepe, Joyce A.
Donohue, Susan E.
Lambrecht, Richard W.
Bonkovsky, Herbert L.
UMass Chan AffiliationsDepartment of Medicine, Division of Hematology/Oncology
Department of Biochemistry and Molecular Pharmacology
Graduate School of Biomedical Sciences
Keywords5-Aminolevulinate Synthetase; Allylisopropylacetamide; Animals; Cells, Cultured; Chick Embryo; Dactinomycin; Deferoxamine; Enzyme Inhibitors; Glutethimide; Heme; Heptanoates; Kinetics; Liver; Metalloporphyrins; Porphobilinogen Synthase; RNA, Messenger; Regression Analysis
Medicine and Health Sciences
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AbstractHepatic 5-aminolevulinic acid synthase, the first and normally rate-controlling enzyme of heme biosynthesis, is regulated by heme. One of the known mechanisms whereby increased cellular heme regulates 5-aminolevulinic acid synthase is by decreasing the stability of its mRNA. In primary cultures of chick embryo liver cells, we tested whether a decrease in cellular heme might increase 5-aminolevulinic acid synthase mRNA stability and whether heme or other metalloporphyrins could reverse this stabilization. We found that: (a) The stability of 5-aminolevulinic acid synthase mRNA was markedly increased by inhibitors of heme biosynthesis, namely, 4,6-dioxoheptanoic acid or deferoxamine; (b) This increased stability of 5-aminolevulinic acid synthase mRNA was reversed by the addition of heme (10 microM) or by the combination of zinc mesoporphyrin (50 nM), an inhibitor of heme oxygenase, and heme (200 nM); (c) Repression of 5-aminolevulinic acid synthase mRNA levels by zinc mesoporphyrin (10 microM) was due to inhibition of heme oxygenase, rather than a direct, heme-like, effect of zinc mesoporphyrin on 5-aminolevulinic acid synthase mRNA; (d) Among the several non-heme metalloporphyrins tested, only zinc mesoporphyrin and chromium mesoporphyrin significantly decreased 5-aminolevulinic acid synthase mRNA without increasing heme oxygenase mRNA.
Eur J Biochem. 1996 Aug 15;240(1):112-7.
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/33040