Distinct effects of phenobarbital and its N-methylated derivative on liver cytochrome P450 induction

Arch Biochem Biophys. 1996 Apr 1;328(1):184-92. doi: 10.1006/abbi.1996.0159.


The relationship between barbiturate structures and their effects on induction of rat cytochrome P450 forms was studied in primary cultured hepatocytes. Treatment of hepatocytes cultured on matrigel with 1 mM barbital, N-methylbarbital, cyclobarbital, hexobarbital, phenobarbital (PB), or mephobarbital (N-methyl-PB) resulted in increased amounts of CYP2B1/2 and CYP2C6 forms. Microsomal CYP3A content was also enhanced by treatment with these barbiturates, except for barbital. Although no relationship was observed between the levels of CYP2B1/2 and CYP3A, ratios of CYP3A/CYP2B1 plus CYP2B2 contents were invariably higher with hepatocytes treated with N-methylated barbiturates than with the nonmethylated analogs. Consistent results were also observed in vivo in rats treated with PB and N-methyl-PB. These results indicate the difference in the structure requirement for induction of CYP2B and CYP3A. In addition, N-methyl-PB was found to suppress PB-mediated induction of CYP2B1. Hepatic levels of CYP2B1 mRNA and protein were increased by treatment with PB or N-methyl-PB alone, but decreased by cotreatment with 1 mM PB and N-methyl-PB. The suppression has been shown to occur at the transcriptional level of the CYP2B1 gene by using a chloramphenicol acetyltransferase reporter-CYP2B1 fused gene system.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Base Sequence
  • Cytochrome P-450 CYP2E1
  • Cytochrome P-450 Enzyme System / biosynthesis*
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Enzyme Induction
  • Gene Expression Regulation, Enzymologic*
  • Hydroxylation
  • Liver / drug effects*
  • Mephobarbital / pharmacology*
  • Microsomes, Liver / metabolism
  • Mixed Function Oxygenases / biosynthesis
  • Molecular Sequence Data
  • Phenobarbital / analogs & derivatives
  • Phenobarbital / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship
  • Testosterone / metabolism


  • Testosterone
  • Mephobarbital
  • Cytochrome P-450 Enzyme System
  • Mixed Function Oxygenases
  • Cytochrome P-450 CYP2E1
  • Phenobarbital