Rifampicin induction of CYP3A4 requires pregnane X receptor cross talk with hepatocyte nuclear factor 4alpha and coactivators, and suppression of small heterodimer partner gene expression.

Title

Rifampicin induction of CYP3A4 requires pregnane X receptor cross talk with hepatocyte nuclear factor 4alpha and coactivators, and suppression of small heterodimer partner gene expression.

Creator

Li Tiangang; Chiang John Y L

Publisher

Drug metabolism and disposition: the biological fate of chemicals

Date

2006
2006-05

Description

Bile acids and drugs activate pregnane X receptor (PXR) to induce CYP3A4, which is the predominant cytochrome P450 enzyme expressed in the liver and intestine and plays a critical role in detoxifying bile acids and drugs, and protecting against cholestasis. The aim of this study is to investigate the molecular mechanism of PXR cross talk with other nuclear receptors and coactivators in regulating human CYP3A4 gene transcription. Rifampicin dose dependently induced the CYP3A4 but inhibited small heterodimer partner (SHP) mRNA expression levels in primary human hepatocytes. Rifampicin strongly stimulated PXR and hepatocyte nuclear factor 4alpha (HNF4alpha) interaction, and CYP3A4 reporter activity, which was further stimulated by peroxisome proliferators-activated receptorgamma co-activator 1alpha (PGC-1alpha) and steroid receptor coactivator-1 (SRC-1) but inhibited by SHP. Mutation of the putative HNF4alpha binding site in the distal xenobiotic responsive element module did not affect CYP3A4 basal promoter activity and synergistic stimulation by PXR and HNF4alpha. Chromatin immunoprecipitation assays revealed that rifampicin-activated PXR recruited HNF4alpha and SRC-1 to the CYP3A4 chromatin. On the other hand, SHP reduced PXR recruitment of HNF4alpha and SRC-1 to the CYP3A4 chromatin. The human SHP promoter was stimulated by HNF4alpha and PGC-1alpha. Upon activation by rifampicin, PXR inhibited SHP promoter activity. Results suggest that PXR strongly induces CYP3A4 gene transcription by interacting with HNF4alpha, SRC-1, and PGC-1alpha. PXR concomitantly inhibits SHP gene transcription and maximizes the PXR induction of the CYP3A4 gene in human livers. Drugs targeted to PXR may be developed for treating cholestatic liver diseases induced by bile acids and drugs.

Subject

Antibiotics; Antitubercular/*pharmacology; Blotting; Cell Line; Chromatin/metabolism; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System/*biosynthesis; Cytoplasmic and Nuclear/*biosynthesis/*drug effects/genetics; Electrophoretic Mobility Shift Assay; Enzyme Induction/drug effects; Glutathione Transferase/metabolism; Hepatocyte Nuclear Factor 4/genetics/*metabolism; Hepatocytes/drug effects/metabolism; Humans; Immunoprecipitation; Messenger/biosynthesis; Plasmids/genetics; Pregnane X Receptor; Receptor Cross-Talk/drug effects; Receptors; Reverse Transcriptase Polymerase Chain Reaction; Rifampin/*pharmacology; RNA; Steroid/*drug effects/genetics; Transfection; Tumor; Western

Rights

Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).

Pages

756–764

Issue

5

Volume

34

Citation

Li Tiangang; Chiang John Y L, “Rifampicin induction of CYP3A4 requires pregnane X receptor cross talk with hepatocyte nuclear factor 4alpha and coactivators, and suppression of small heterodimer partner gene expression.,” NEOMED Bibliography Database, accessed June 22, 2021, https://neomed.omeka.net/items/show/4519.

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