title: Succinylacetone inhibits delta-aminolevulinate dehydratase and potentiates the drug and steroid induction of delta-aminolevulinate synthase in liver.
abstract: Succinylacetone, an abnormal metabolite of the tyrosine metabolic pathway, is produced in patients with hereditary tyrosinemia because of a genetic deficiency of fumarylacetoacetase. This metabolite greatly inhibits the activity of ALA dehydratase and accounts for the elevated excretion of ALA in urine in this disease. We have studied the effects of succinylacetone on heme synthesis in cultured avian hepatocytes and on the activity of purified ALA dehydratase from normal human erythrocytes and from mouse liver. Succinylacetone markedly inhibited ALA dehydratase in a competitive manner. The compound also decreased cellular heme and cytochrome P-450 content, and greatly potentiated the drug and steroid induction of ALA synthase in primary cultures of liver cells. Four patients with hereditary tyrosinemia were found to have markedly low erythrocyte ALA dehydratase activity and elevated concentrations of an inhibitor of the enzyme in urine. The concentration of the inhibitor, i.e., succinylacetone, was reduced and the erythrocyte ALA dehydratase activity was restored toward normal in one patient treated with a diet formula low in tyrosine and phenylalanine. Hereditary tyrosinemia is a genetic disease of unique interest since an abnormal metabolite, succinylacetone, produced by the primary enzymatic deficiency in this disorder, profoundly inhibits an enzyme, ALA dehydratase, involved in heme biosynthesis. This enzyme inhibition results in a clinical and biochemical mimicry of AIP in some patients.
mesh_terms: D000624:5-Aminolevulinate Synthetase / Q000096:biosynthesis*; D000592:Amino Acid Metabolism, Inborn Errors / Q000097:blood*; D000818:Animals; D002642:Chick Embryo; D004912:Erythrocytes / Q000201:enzymology*; D006537:Heptanoates / Q000494:pharmacology*; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D008099:Liver / Q000166:cytology / Q000201:enzymology*; D051379:Mice; D008807:Mice, Inbred BALB C; D000623:Porphobilinogen Synthase / Q000037:antagonists & inhibitors*; D014443:Tyrosine / Q000097:blood*
chemical_list: D006537:Heptanoates; D006538:Heptanoic Acids; D014443:Tyrosine; C020804:succinylacetone; D000624:5-Aminolevulinate Synthetase; D000623:Porphobilinogen Synthase