Dataset Information


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

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). 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.


PROVIDER: S-EPMC3372740 | BioStudies | 2012-01-01T00:00:00Z

REPOSITORIES: biostudies

Similar Datasets

2019-01-01 | S-EPMC6421094 | BioStudies
2012-01-01 | S-EPMC3449269 | BioStudies
1000-01-01 | S-EPMC3362786 | BioStudies
2008-08-23 | E-GEOD-12489 | ArrayExpress
| S-EPMC2721020 | BioStudies
2018-01-01 | S-EPMC5960625 | BioStudies
2010-05-16 | E-GEOD-12537 | ArrayExpress
2008-08-23 | E-GEOD-12509 | ArrayExpress
2013-01-01 | S-EPMC3634023 | BioStudies
2015-01-01 | S-EPMC4324004 | BioStudies