Mechanism of allylisopropylacetamide-induced increase of δ-aminolevulinate synthetase in liver mitochondria: V. Mechanism of regulation by hemin of the level of δ-aminolevulinate synthetase in rat liver mitochondria

Abstract

Increased synthesis of hepatic ALA 2 2 Abbreviations: ALA, δ-aminolevulinic acid; AIA, allylisopropylacetamide. synthetase was induced in rats by administration of AIA 2 and effects of injection of hemin on the level of hepatic ALA synthetase in different subcellular fractions of rat liver were studied at various stages of induction. When hemin was injected to rats at an initial stage of induction, AIA-induced increase of ALA synthetase was strongly suppressed in either mitochondrial or extramitochondrial fraction. However, when hydrocortisone was administered to animals together with AIA, induction of ALA synthetase was not appreciably affected by hemin. On the other hand, when hemin was injected to animals at a later stage of induction, ALA synthetase level in the extramitochondrial fraction increased markedly, whereas the level in mitochondria decreased sharply and therefore the total activity of ALA synthetase in the liver was not significantly decreased. ALA synthetase accumulating in the soluble fraction after hemin injection was of the “soluble form”. Unlike hemin, neither actinomycin D nor cycloheximide brought about the increase of level of extramitochondrial ALA synthetase. Further, when hemin was injected to AIA-treated rats, the apparent half-life time of ALA synthetase in the soluble fraction was markedly lengthened. Bilirubin and ALA exhibited essentially similar effects to those of hemin. It was assumed that hemin controls the level of ALA synthetase in liver mitochondria firstly by suppressing the initiation of induction of ALA synthetase and secondly by inhibiting the conversion of the “soluble form” of ALA synthetase into the “mitochondrial” ALA synthetase.