Role of CYP3A4 in the regulation of the aryl hydrocarbon receptor by omeprazole sulphide

被引:42
作者
Gerbal-Chaloin, S
Pichard-Garcia, L
Fabre, JM
Sa-Cunha, A
Poellinger, L
Maurel, P
Daujat-Chavanieu, M
机构
[1] INSERM, U632, F-34293 Montpellier, France
[2] Univ Montpellier 1, EA3768, F-34000 Montpellier, France
[3] Hop St Eloi, Serv Chirg Digest, F-34295 Montpellier, France
[4] Hop Haut Leveque, Serv Chirurg Digest, F-33604 Pessac, France
[5] Karolinska Inst, Dept Cell & Mol Biol, S-17177 Stockholm, Sweden
关键词
CYP3A4; aryl hydrocarbon receptor; preganae X receptor; omeprazole-sulphide; rifampicin; antagonist; agonist; cross-talk;
D O I
10.1016/j.cellsig.2005.07.007
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Cross-talk between nuclear receptors involved in the control of drug metabolism is being increasingly recognised as a source of drug side effects. Omeprazole is a well known activator of the aryl hydrocarbon receptor (AhR). We investigated the regulation of AhR by omeprazole-sulphide, a degradation metabolite of omeprazole, using CYP1A mRNA induction, reporter gene assay, receptor DNA binding, ligand binding, nuclear translocation, trypsin digests, and drug metabolism analysis in mouse Hepa-1c1c7, human HepG2 cells and primary human hepatocytes. Omeprazole-sulphide is a pure antagonist of AhR in Hepa-1c1c7 and HepG2 hepatoma cell lines. In Hepa-1c1c7 cells, omeprazole-sulphide is a ligand of AhR, inhibits AhR activation to a DNA-binding form, induces a specific pattern of AhR trypsin digestion and inhibits AhR nuclear translocation and subsequent degradation in response to 2,3,7,8-tetrachlorodibenzo-p-dioxin. However, in highly differentiated primary human hepatocytes treated with rifampicin an agonist of the pregnane X receptor (PXR), orneprazole-sulphide behaves as an agonist of AhR. Inhibition of drug metabolizing enzymes by ketoconazole restores the antagonist effect of omeprazole-sulphide. Metabolic LC/MS analysis reveals that omeprazole-sulphide (AhR antagonist) is efficiently converted to omeprazole (AhR activator) by cytochrome P450 CYP3A4, a target gene of PXR, in primary human hepatocytes but not in hepatoma cells in which PYR is not expressed. This report provides the first evidence for a cross-talk between PXR/CYP3A4 and AhR. In addition, it clearly shows that conclusions drawn from experiments carried out in cell lines may lead to erroneous in vivo predictions in man. (c) 2005 Elsevier Inc. All rights reserved.
引用
收藏
页码:740 / 750
页数:11
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