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Titolo:
The orphan human pregnane X receptor mediates the transcriptional activation of CYP3A4 by rifampicin through a distal enhancer module
Autore:
Goodwin, B; Hodgson, E; Liddle, C;
Indirizzi:
Westmead Hosp, Univ Sydney, Dept Clin Pharmacol, Westmead, NSW 2145, Australia Westmead Hosp Westmead NSW Australia 2145 , Westmead, NSW 2145, Australia Westmead Hosp, Univ Sydney, Storr Liver Unit, Westmead, NSW 2145, Australia Westmead Hosp Westmead NSW Australia 2145 , Westmead, NSW 2145, Australia
Titolo Testata:
MOLECULAR PHARMACOLOGY
fascicolo: 6, volume: 56, anno: 1999,
pagine: 1329 - 1339
SICI:
0026-895X(199912)56:6<1329:TOHPXR>2.0.ZU;2-8
Fonte:
ISI
Lingua:
ENG
Soggetto:
NUCLEAR RECEPTOR; CYTOCHROME-P450 3A4; HUMAN HEPATOCYTES; PRIMARY CULTURES; GLUCOCORTICOID RECEPTOR; SIGNALING PATHWAY; DRUG-INTERACTIONS; GENE; EXPRESSION; PROMOTER;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
41
Recensione:
Indirizzi per estratti:
Indirizzo: Liddle, C Westmead Hosp, Univ Sydney, Dept Clin Pharmacol, Westmead, NSW 2145, Australia Westmead Hosp Westmead NSW Australia 2145 , NSW 2145, Australia
Citazione:
B. Goodwin et al., "The orphan human pregnane X receptor mediates the transcriptional activation of CYP3A4 by rifampicin through a distal enhancer module", MOLEC PHARM, 56(6), 1999, pp. 1329-1339

Abstract

Cytochrome P-450 3A4 (CYP3A4), the predominant cytochrome P-450 expressed in adult human liver, is subject to transcriptional induction by a variety of structurally unrelated xenobiotics, including the antibiotic rifampicin. The molecular mechanisms underlying this phenomenon are poorly understood. We transfected a human liver-derived cell line (HepG2) with various CYP3A4-luciferase reporter gene constructs containing a nested set of 5'-deletions of the CYP3A4 5'-flanking region. Rifampicin-inducible transcription of the reporter gene was observed only with the longest construct, which encompassed bases -13000 to +53 of CYP3A4 (3-fold induction). The responsive region was functional regardless of its position or orientation relative to theproximal promoter of CYP3A4 and was capable of conferring rifampicin-inducible expression on a heterologous promoter. Further deletion mutants localized the induction to bases -7836 to -7607. In vitro DNase I footprint analysis of this region revealed four protected sites (FP1, FP2, FP3, and FP4). Two of these sites, FP3 (bases -7738 to -7715) and FP4 (bases -7698 to -7682), overlapped binding motifs for the orphan human pregnane X receptor (hPXR). Cotransfection of responsive constructs with a hPXR expression vector substantially increased the rifampicin-inducibility to similar to 50-fold. In addition, the rifampicin-responsive constructs were strongly activated bya range of CYP3A inducers. Finally, we demonstrate cooperativity between elements within the distal enhancer region and cis-acting elements in the proximal promoter of CYP3A4. Our results provide evidence for the existence of a potent enhancer module, 8 kb distal to the transcription start point, which mediates the transcriptional induction of CYP3A4 by activators of hPXR.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 28/01/20 alle ore 21:05:01