Effects of intravenous administration of various amounts of hemin on δ-aminolevulinate (ALA) synthase and on the degree of heme saturation of tryptophan pyrrolase were examined in the liver of rats treated or untreated with allylisopropylacetamide (AIA). In AIA-treated animals, the activity of ALA synthase decreased immediately and rapidly in the mitochondria but increased markedly in the cytosol after hemin injection, and the extents of the change of the ALA synthase activity observed after injection of various amounts of hemin showed a good correlation with the change of degree of heme saturation of tryptophan pyrrolase which is supposed to reflect the intracellular heme concentration. The dose of hemin which caused a nearly full saturation of tryptophan pyrrolase also exerted maximal effects on ALA synthase. The intracellular translocation of ALA synthase may be inhibited by intracellular heme at concentrations lower than those necessary to achieve a full saturation of tryptophan pyrrolase. In AIA-untreated normal animals, the administration of similar doses of hemin inhibited not only intracellular translocation but also synthesis of ALA synthase, and the extent of the inhibition of synthesis was also closely related to the degree of heme saturation of tryptophan pyrrolase. It may be assumed that the inhibition by heme of both the synthesis and the intracellular translocation of ALA synthase would contribute to the feedback regulation of heme biosynthesis under physiological conditions. To significantly inhibit the synthesis of ALA synthase in AIA-treated rats, however, a much larger dose of hemin than those necessary to fully saturate tryptophan pyrrolase was required, suggesting that the synthetic machinery of ALA synthase might be made less sensitive to heme when animals were treated with AIA.
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