Aryl hydrocarbon receptor-mediated induction of microsomal drug-metabolizing enzyme activity by indirubin and indigo

Biochem Biophys Res Commun. 2004 May 28;318(2):571-8. doi: 10.1016/j.bbrc.2004.04.066.

Abstract

Indirubin and indigo, which are thought to be natural ligands for aryl hydrocarbon receptor (AhR), showed marked AhR ligand activities in a reporter gene assay using recombinant yeast. Their activities were comparable with or more potent than that of 2,3,7,8-tetrachlorodibenzo-p-dioxin. When indirubin and indigo were administered to mice, ethoxyresorufin-O-dealkylase and methoxyresorufin-O-dealkylase activities in the liver were increased, but subsequently decreased within 2 days. Indirubin was more potent than indigo. Levels of cytochrome P450 1A1/2 proteins and mRNAs in the liver of mice dosed with indirubin were also enhanced. These enhancing effects of indirubin and indigo were not observed in AhR knock-out mice. Ethoxyresorufin-O-dealkylase and methoxyresorufin-O-dealkylase activities in rat hepatocytes and HepG2 cells were enhanced by the addition of indirubin or indigo, but less potently than by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Indigocarmine, a sulfate derivative of indigo, which is used as food additive, did not show these inducing effects on drug-metabolizing enzymes. Our results suggest that indirubin and indigo act as inducers for cytochrome P450 1A1/2 mediated by AhR in mammals in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cytochrome P-450 CYP1A1 / biosynthesis
  • Cytochrome P-450 CYP1A1 / genetics
  • Cytochrome P-450 CYP1A2 / biosynthesis
  • Cytochrome P-450 CYP1A2 / genetics
  • Cytochrome P-450 Enzyme System / biosynthesis*
  • Cytochrome P-450 Enzyme System / genetics
  • Cytochrome P-450 Enzyme System / metabolism
  • Dose-Response Relationship, Drug
  • Enzyme Induction / drug effects
  • Hepatocytes / cytology
  • Hepatocytes / metabolism
  • Indigo Carmine
  • Indoles / metabolism
  • Indoles / pharmacology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / enzymology*
  • RNA, Messenger / biosynthesis
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Aryl Hydrocarbon / genetics
  • Receptors, Aryl Hydrocarbon / metabolism*
  • Yeasts / genetics
  • Yeasts / metabolism

Substances

  • Indoles
  • RNA, Messenger
  • Receptors, Aryl Hydrocarbon
  • Cytochrome P-450 Enzyme System
  • Indigo Carmine
  • Cytochrome P-450 CYP1A1
  • Cytochrome P-450 CYP1A2
  • indirubin