Effects of atorvastatin metabolites on induction of drug-metabolizing enzymes and membrane transporters through human pregnane X receptor

Br J Pharmacol. 2012 Mar;165(5):1595-608. doi: 10.1111/j.1476-5381.2011.01665.x.


Background and purpose: Atorvastatin metabolites differ in their potential for drug interaction because of differential inhibition of drug-metabolizing enzymes and transporters. We here investigate whether they exert differential effects on the induction of these genes via activation of pregnane X receptor (PXR) and constitutive androstane receptor (CAR).

Experimental approach: Ligand binding to PXR or CAR was analysed by mammalian two-hybrid assembly and promoter/reporter gene assays. Additionally, surface plasmon resonance was used to analyse ligand binding to CAR. Primary human hepatocytes were treated with atorvastatin metabolites, and mRNA and protein expression of PXR-regulated genes was measured. Two-hybrid co-activator interaction and co-repressor release assays were utilized to elucidate the molecular mechanism of PXR activation.

Key results: All atorvastatin metabolites induced the assembly of PXR and activated CYP3A4 promoter activity. Ligand binding to CAR could not be proven. In primary human hepatocytes, the para-hydroxy metabolite markedly reduced or abolished induction of cytochrome P450 and transporter genes. While significant differences in co-activator recruitment were not observed, para-hydroxy atorvastatin demonstrated only 50% release of co-repressors.

Conclusions and implications: Atorvastatin metabolites are ligands of PXR but not of CAR. Atorvastatin metabolites demonstrate differential induction of PXR target genes, which results from impaired release of co-repressors. Consequently, the properties of drug metabolites have to be taken into account when analysing PXR-dependent induction of drug metabolism and transport. The drug interaction potential of the active metabolite, para-hydroxy atorvastatin, might be lower than that of the parent compound.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aryl Hydrocarbon Hydroxylases / biosynthesis
  • Aryl Hydrocarbon Hydroxylases / genetics
  • Aryl Hydrocarbon Hydroxylases / metabolism
  • Atorvastatin
  • Cell Line, Tumor
  • Co-Repressor Proteins / metabolism
  • Cytochrome P-450 CYP2B6
  • Cytochrome P-450 CYP3A / biosynthesis*
  • Cytochrome P-450 CYP3A / genetics*
  • Cytochrome P-450 CYP3A / metabolism
  • Cytochrome P-450 Enzyme System / biosynthesis
  • Cytochrome P-450 Enzyme System / genetics
  • Cytochrome P-450 Enzyme System / metabolism
  • Drug Interactions
  • Genes, Reporter / drug effects
  • Hep G2 Cells
  • Hepatocytes / drug effects
  • Hepatocytes / enzymology
  • Hepatocytes / metabolism
  • Heptanoic Acids / metabolism
  • Heptanoic Acids / pharmacology*
  • Humans
  • Ligands
  • Membrane Transport Proteins / biosynthesis*
  • Membrane Transport Proteins / genetics
  • Membrane Transport Proteins / metabolism
  • Oxidoreductases, N-Demethylating / biosynthesis
  • Oxidoreductases, N-Demethylating / genetics
  • Oxidoreductases, N-Demethylating / metabolism
  • Pregnane X Receptor
  • Promoter Regions, Genetic
  • Pyrroles / metabolism
  • Pyrroles / pharmacology*
  • RNA, Messenger / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Receptors, Steroid / biosynthesis*
  • Receptors, Steroid / genetics*
  • Receptors, Steroid / metabolism


  • Co-Repressor Proteins
  • Heptanoic Acids
  • Ligands
  • Membrane Transport Proteins
  • Pregnane X Receptor
  • Pyrroles
  • RNA, Messenger
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Steroid
  • constitutive androstane receptor
  • Cytochrome P-450 Enzyme System
  • Atorvastatin
  • Aryl Hydrocarbon Hydroxylases
  • CYP2B6 protein, human
  • Cytochrome P-450 CYP2B6
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Oxidoreductases, N-Demethylating