Hoffart, E. and Ghebreghiorghis, L. and Nussler, A. K. and Thasler, W. E. and Weiss, T. S. and Schwab, M. and Burk, O. (2012) Effects of atorvastatin metabolites on induction of drug-metabolizing enzymes and membrane transporters through human pregnane X receptor. BRITISH JOURNAL OF PHARMACOLOGY, 165 (5). pp. 1595-1608. ISSN 0007-1188,
Full text not available from this repository. (Request a copy)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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | CONSTITUTIVE ANDROSTANE RECEPTOR; ACTIVATED PROTEIN-KINASE; COA REDUCTASE INHIBITORS; HUMAN HEPATOCYTES; LACTONE FORMS; MDR1 EXPRESSION; P-GLYCOPROTEIN; ACID; PHARMACOKINETICS; VARIANTS; atorvastatin; metabolites; para-hydroxy atorvastatin; PXR; CAR; induction; drug interaction |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Kinder- und Jugendmedizin |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 19 May 2020 04:28 |
| Last Modified: | 19 May 2020 04:28 |
| URI: | https://pred.uni-regensburg.de/id/eprint/19124 |
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