Heme may not be a positive regulator of cytochrome-P450 gene expression.
It has been proposed that transcription of cytochrome-P450 genes is positively regulated by heme, the prosthetic group of cytochrome-P450 proteins. We have investigated this proposal in rats treated with succinylacetone, a known specific inhibitor of the heme biosynthetic pathway. While 2-allyl-2-isopropylacetamide, phenobarbitone, dexamethasone, beta-naphthoflavone and clofibrate induced specific cytochrome-P450-mRNA species in rat liver, the levels of these induced mRNAs were not affected by succinylacetone administration. Synthesis of the first enzyme of the heme biosynthetic pathway, 5-aminolevulinate synthase, is known to be regulated by the end-product heme, with heme inhibiting 5-aminolevulinate-synthase-gene transcription. Hepatic 5-aminolevulinate-synthase mRNA was induced by drugs and the level increased further by succinylacetone. Furthermore, treatment of rats with succinylacetone alone resulted in elevated levels of 5-aminolevulinate-synthase mRNA but did not affect cytochrome-P450-mRNA levels. The results show that while lowered heme levels lead to an increase in 5-aminolevulinate-synthase-mRNA synthesis there is no effect on cytochrome-P450-mRNA levels, implying that heme is not required for the cytochrome-P450-gene transcription.
Srivastava
G
G
Department of Biochemistry, University of Adelaide, Australia.
Bawden
M J
MJ
Hansen
A J
AJ
May
B K
BK
D000624:5-Aminolevulinate Synthetase / Q000096:biosynthesis / Q000235:genetics; D000502:Allylisopropylacetamide / Q000494:pharmacology; D000818:Animals; D001571:Benzoflavones / Q000494:pharmacology; D002994:Clofibrate / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics*; D003907:Dexamethasone / Q000494:pharmacology; D004790:Enzyme Induction; D005786:Gene Expression Regulation / Q000187:drug effects*; D005796:Genes / Q000187:drug effects; D006418:Heme / Q000096:biosynthesis / Q000502:physiology*; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D010634:Phenobarbital / Q000494:pharmacology; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics; D051381:Rats; D011919:Rats, Inbred Strains; D012016:Reference Values; D014158:Transcription, Genetic / Q000187:drug effects*; D019324:beta-Naphthoflavone
D001571:Benzoflavones; D012333:RNA, Messenger; D000502:Allylisopropylacetamide; D006418:Heme; D019324:beta-Naphthoflavone; D003907:Dexamethasone; D003577:Cytochrome P-450 Enzyme System; D000624:5-Aminolevulinate Synthetase; D002994:Clofibrate; D010634:Phenobarbital