Heme may not be a positive regulator of cytochrome‐P450 gene expression

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Abstract
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, β‐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.