Negative regulation by dexamethasone of fluvastatin-inducible CYP2B expression in primary cultures of rat hepatocytes: role of CYP3A

Biochem Pharmacol. 1998 May 1;55(9):1435-43. doi: 10.1016/s0006-2952(97)00658-8.


Fluvastatin (Fluva), a synthetic inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, induces CYP2B1/2 in rat liver and primary cultured rat hepatocytes. However, the overall profile of CYP induction, which includes induction of CYP4A, suggests that Fluva is not a typical "phenobarbital (PB)-like" inducer. Several treatments affecting diverse cell signaling pathways have been reported to modify PB-inducible CYP2B expression in primary cultured rat hepatocytes. We examined the effects of selected treatments on the ability of Fluva to induce CYP2B1/2 mRNA. Only dexamethasone (Dex) produced effects on Fluva-inducible CYP2B1/2 mRNA expression that differed from those produced on PB-inducible CYP2B1/2 mRNA expression. Dex concentrations up to 10(-7) M of potentiated PB (10(-4) M)-mediated CYP2B1/2 mRNA induction, while higher Dex concentrations produced a progressive reduction in PB-induced CYP2B1/2 mRNA levels. By contrast, Dex concentrations up to 10(-8) M had no effect on Fluva (3 x 10(-5) M)-induced CYP2B1/2 mRNA levels, while Dex concentrations of 10(-7) M and higher markedly suppressed Fluva-mediated CYP2B1/2 mRNA induction. The concentrations of several glucocorticoids that produced suppression of Fluva-induced CYP2B1/2 mRNA levels were the same concentrations that induced CYP3A mRNA. Treatment with pregnenolone 16 alpha-carbonitrile also produced a concentration-dependent suppression of Fluva-induced CYP2B1/2 mRNA levels. Dex-mediated suppression of Fluva-induced CYP2B1/2 mRNA was concentration-dependently reversed when hepatocytes were cotreated with troleandomycin, a selective CYP3A inhibitor. The amounts of Fluva detected in culture medium and cells were reduced significantly when hepatocytes were incubated with Dex. However, Dex-mediated suppression of Fluva-induced CYP2B1/2 mRNA expression was not overcome when hepatocytes were incubated with Fluva concentrations greater than 3 x 10(-5) M, suggesting that mechanisms other than CYP3A-catalyzed metabolism may contribute to Dex-mediated suppression of Fluva-induced CYP2B1/2 expression.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Aryl Hydrocarbon Hydroxylases*
  • Cells, Cultured
  • Cytochrome P-450 CYP2B1 / biosynthesis
  • Cytochrome P-450 CYP2B1 / genetics*
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme System / biosynthesis
  • Cytochrome P-450 Enzyme System / genetics*
  • Cytochrome P-450 Enzyme System / metabolism*
  • Dexamethasone / pharmacology*
  • Dose-Response Relationship, Drug
  • Enzyme Induction / drug effects
  • Enzyme Inhibitors / pharmacology*
  • Fatty Acids, Monounsaturated / pharmacology*
  • Fluvastatin
  • Gene Expression Regulation, Enzymologic / drug effects*
  • Hydroxymethylglutaryl CoA Reductases / genetics
  • Indoles / pharmacology*
  • Kinetics
  • Liver / cytology
  • Liver / enzymology*
  • Male
  • Oxidoreductases, N-Demethylating / biosynthesis
  • Oxidoreductases, N-Demethylating / genetics
  • Oxidoreductases, N-Demethylating / metabolism*
  • RNA, Messenger / genetics
  • Rats
  • Rats, Sprague-Dawley
  • Steroid Hydroxylases / biosynthesis
  • Steroid Hydroxylases / genetics*
  • Transcription, Genetic / drug effects*


  • Enzyme Inhibitors
  • Fatty Acids, Monounsaturated
  • Indoles
  • RNA, Messenger
  • Fluvastatin
  • Dexamethasone
  • Cytochrome P-450 Enzyme System
  • Hydroxymethylglutaryl CoA Reductases
  • Steroid Hydroxylases
  • Aryl Hydrocarbon Hydroxylases
  • Cytochrome P-450 CYP2B1
  • Cytochrome P-450 CYP3A
  • steroid 16-beta-hydroxylase
  • Oxidoreductases, N-Demethylating