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

Biochem J. 1980 Sep 15;190(3):519-26. doi: 10.1042/bj1900519.

Abstract

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.

MeSH terms

  • 5-Aminolevulinate Synthetase / biosynthesis*
  • Allylisopropylacetamide / pharmacology
  • Animals
  • Chick Embryo
  • Cytochrome P-450 Enzyme System / metabolism*
  • Deferoxamine / pharmacology
  • Dicarbethoxydihydrocollidine / pharmacology
  • Enzyme Induction / drug effects
  • Heme / metabolism*
  • Hemin / pharmacology
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / enzymology*
  • Phenobarbital / pharmacology
  • Porphyrias / chemically induced
  • Proadifen / pharmacology

Substances

  • Allylisopropylacetamide
  • Heme
  • Dicarbethoxydihydrocollidine
  • Hemin
  • Cytochrome P-450 Enzyme System
  • Proadifen
  • 5-Aminolevulinate Synthetase
  • Deferoxamine
  • Phenobarbital