Evidence that in chick embryos destruction of hepatic microsomal cytochrome P-450 haem is a general mechanism of induction of delta-aminolaevulinate synthase by porphyria-causing drugs.
A variety of prophyrinogenic compounds were tested for their effect in ovo on chick-embryo liver microsomal cytochrome P-450 haem concentration and mitochondrial delta-aminolaevulinate synthase activity. With all drugs tested, there was a 30--50% decrease in cytochrome P-450 haem concentration within 1 h of treatment, and this was closely followed by an increase in delta-aminolaevulinate synthase activity. The relationship was independent of the extent of enzyme induction and is consistent with the proposal that drug-mediated destruction of cytochrome P-450 haem is the primary mechanism of induction of delta-aminolaevulinate synthase. After induction, synthesis of delta-aminolaevulinate synthase could be maintained by inhibiting further haem synthesis. These studies suggest that induction of porphyria is a combination of two distinct processes: (a) induction of delta-aminolaevulinate synthase synthesis by destruction of cytochrome P-450 haem and consequent depletion of cellular free haem; (b) maintenance of continued delta-aminolaevulinate synthase synthesis by preventing replenishment of cellular haem either by inhibiting haem synthesis and/or by promoting continuous removal of newly synthesized haem.
D000624:5-Aminolevulinate Synthetase / Q000096:biosynthesis*; D000502:Allylisopropylacetamide / Q000494:pharmacology; D000818:Animals; D002642:Chick Embryo; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003676:Deferoxamine / Q000494:pharmacology; D003997:Dicarbethoxydihydrocollidine / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D006418:Heme / Q000378:metabolism*; D006427:Hemin / Q000494:pharmacology; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D010634:Phenobarbital / Q000494:pharmacology; D011164:Porphyrias / Q000139:chemically induced; D011335:Proadifen / Q000494:pharmacology
D000502:Allylisopropylacetamide; D006418:Heme; D003997:Dicarbethoxydihydrocollidine; D006427:Hemin; D003577:Cytochrome P-450 Enzyme System; D011335:Proadifen; D000624:5-Aminolevulinate Synthetase; D003676:Deferoxamine; D010634:Phenobarbital