Journal
DRUG METABOLISM AND DISPOSITION
Volume 34, Issue 5, Pages 756-764Publisher
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/dmd.105.007575
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- NIDDK NIH HHS [R01 DK044442, R56 DK044442, R01 DK058379, DK31584, DK44442] Funding Source: Medline
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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 4 alpha (HNF4 alpha) interaction, and CYP3A4 reporter activity, which was further stimulated by peroxisome proliferators- activated receptor gamma co-activator 1 alpha (PGC-1 alpha) and steroid receptor coactivator-1 (SRC-1) but inhibited by SHP. Mutation of the putative HNF4 alpha binding site in the distal xenobiotic responsive element module did not affect CYP3A4 basal promoter activity and synergistic stimulation by PXR and HNF4 alpha. Chromatin immunoprecipitation assays revealed that rifampicin-activated PXR recruited HNF4 alpha and SRC-1 to the CYP3A4 chromatin. On the other hand, SHP reduced PXR recruitment of HNF4 alpha and SRC-1 to the CYP3A4 chromatin. The human SHP promoter was stimulated by HNF4 alpha and PGC-1 alpha. Upon activation by rifampicin, PXR inhibited SHP promoter activity. Results suggest that PXR strongly induces CYP3A4 gene transcription by interacting with HNF4 alpha, SRC-1, and PGC-1 alpha. 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.
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