Effect of succinylacetone on heme and cytochrome P450 synthesis in hepatocyte culture

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Abstract
The effects of succinylacetone, a tyrosine metabolite, on the hepatic biosynthesis of heme and cytochrome P450 were studied in primary culture of chick embryo hepatocytes. Succinylacetone potentiated the phenobarbital-mediated induction of delta-aminolevulinate synthase, strongly inhibited porphobilinogen synthase activity, reduced cellular heme concentration and impaired induction of cytochrome P450. Enhanced induction of delta-aminolevulinate synthase and decreased cytochrome P450 induction may be explained by the succinylacetone-mediated inhibition of porphobilinogen synthase and the subsequent depletion of intracellular heme, since these effects of succinylacetone were reversed by addition of heme. These results suggest clinical implications for patients with tyrosinemia, who accumulate succinylacetone.