Suppression of the expression of the CYP2B1/2 gene by retinoic acids

Biochem Biophys Res Commun. 2000 Oct 14;277(1):66-71. doi: 10.1006/bbrc.2000.3620.

Abstract

The effects of 5alpha-androsten-3alpha-ol (ASE), and retinoic acids (RAs) and their precursors on the phenobarbital (PB)-mediated induction of CYP2B1 and 2B2 were examined in cultured rat hepatocytes. Two isomers of RA, 9-cis- and all-trans-RA, suppressed markedly the effect of PB on CYP2B1/2 expression, while ASE had no suppressive effect. The effect of 9-cis-RA appeared at a lower concentration than the all-trans-isomer, indicating the dominant action of the former isomer. Suppression with 9-cis-retinal was also observed, but all-trans-retinol and -retinal were without effect. These results suggest that: (1) ASE, an inverse agonist for the constitutive androstane receptor (CAR), does not play a major role in the suppression of the CYP2B; (2) 9-cis-RA suppresses CYP2B induction by reducing ligand-free retinoid X-receptors (RXR) available for dimerization with the CAR; and (3) enzymes responsible for RA formation play an important role in the mechanism governing CYP2B regulation.

MeSH terms

  • Androstenols / pharmacology
  • Animals
  • Aryl Hydrocarbon Hydroxylases*
  • Cells, Cultured
  • Constitutive Androstane Receptor
  • Cytochrome P-450 CYP2B1 / antagonists & inhibitors
  • Cytochrome P-450 CYP2B1 / genetics*
  • Cytochrome P-450 CYP2B1 / metabolism
  • Cytochrome P-450 Enzyme Inhibitors
  • Cytochrome P-450 Enzyme System / genetics*
  • Cytochrome P-450 Enzyme System / metabolism
  • Dimerization
  • Dose-Response Relationship, Drug
  • Down-Regulation / drug effects
  • Enzyme Induction / drug effects*
  • Hepatocytes / enzymology
  • Hepatocytes / metabolism
  • Immunoblotting
  • Isomerism
  • Ligands
  • Liver / cytology
  • Liver / enzymology
  • Liver / metabolism
  • Male
  • Phenobarbital / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Receptors, Retinoic Acid / metabolism
  • Retinoid X Receptors
  • Steroid Hydroxylases / antagonists & inhibitors
  • Steroid Hydroxylases / genetics*
  • Steroid Hydroxylases / metabolism
  • Transcription Factors / metabolism
  • Tretinoin / pharmacology*

Substances

  • Androstenols
  • Constitutive Androstane Receptor
  • Cytochrome P-450 Enzyme Inhibitors
  • Ligands
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Retinoic Acid
  • Retinoid X Receptors
  • Transcription Factors
  • androst-5-en-3-ol
  • Tretinoin
  • Cytochrome P-450 Enzyme System
  • Steroid Hydroxylases
  • Aryl Hydrocarbon Hydroxylases
  • Cytochrome P-450 CYP2B1
  • steroid 16-beta-hydroxylase
  • Phenobarbital