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.