Back to Search
Start Over
Effects of atorvastatin metabolites on induction of drug-metabolizing enzymes and membrane transporters through human pregnane X receptor.
- Source :
-
British journal of pharmacology [Br J Pharmacol] 2012 Mar; Vol. 165 (5), pp. 1595-608. - Publication Year :
- 2012
-
Abstract
- 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).<br />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.<br />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.<br />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.<br /> (© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.)
- Subjects :
- Aryl Hydrocarbon Hydroxylases biosynthesis
Aryl Hydrocarbon Hydroxylases genetics
Aryl Hydrocarbon Hydroxylases metabolism
Atorvastatin
Cell Line, Tumor
Co-Repressor Proteins metabolism
Constitutive Androstane Receptor
Cytochrome P-450 CYP2B6
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
Humans
Ligands
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
RNA, Messenger genetics
Receptors, Cytoplasmic and Nuclear metabolism
Receptors, Steroid metabolism
Cytochrome P-450 CYP3A biosynthesis
Cytochrome P-450 CYP3A genetics
Heptanoic Acids pharmacology
Membrane Transport Proteins biosynthesis
Pyrroles pharmacology
Receptors, Steroid biosynthesis
Receptors, Steroid genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5381
- Volume :
- 165
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- British journal of pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 21913896
- Full Text :
- https://doi.org/10.1111/j.1476-5381.2011.01665.x