Regulation of heme biosynthesis in chick embryo liver cells.
According to current evidence heme controls the heme biosynthetic pathway primarily by controlling translocation of inactive pre-ALA-S from the cytosol into the mitochondrion, where ALA-S is active. A secondary mechanism involves inhibition by heme of transcription of the ALA-S gene. Porphyrinogenic drugs act by lowering a regulatory "free heme pool" by three different mechanisms: (a) by mechanism-based inactivation of cytochrome P-450 resulting in N-alkylprotoporphyrin formation and ferrochelatase inhibition, (b) by mechanism-based inactivation of cytochrome P-450 resulting in continuous heme destruction, (c) by enhanced generation of active oxygen species which interact with an endogenous substrate to form an inhibitor of uroporphyrinogen decarboxylase. It is also possible that porphyrinogenic drugs may exert a direct effect on the nucleus to increase formation of ALA-S mRNA.
Marks
G S
GS
Department of Pharmacology and Toxicology, Queen's University, Kingston, Ontario, Canada.
Mackie
J E
JE
McCluskey
S A
SA
Riddick
D S
DS
D000624:5-Aminolevulinate Synthetase / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D002642:Chick Embryo; D004790:Enzyme Induction; D005246:Feedback; D005786:Gene Expression Regulation / Q000187:drug effects; D006418:Heme / Q000096:biosynthesis* / Q000235:genetics; D008930:Mitochondria, Liver / Q000378:metabolism*; D008954:Models, Biological; D011166:Porphyrins / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects
D011166:Porphyrins; D011500:Protein Synthesis Inhibitors; D006418:Heme; D000624:5-Aminolevulinate Synthetase