The repressed nuclear receptor CAR responds to phenobarbital in activating the human CYP2B6 gene - PubMed (original) (raw)

. 1999 Mar 5;274(10):6043-6.

doi: 10.1074/jbc.274.10.6043.

Affiliations

• PMID: 10037683
• DOI: 10.1074/jbc.274.10.6043

Free article

The repressed nuclear receptor CAR responds to phenobarbital in activating the human CYP2B6 gene

T Sueyoshi et al. J Biol Chem. 1999.

Free article

Abstract

The endogenous CYP2B6 gene becomes phenobarbital (PB) inducible in androstenol-treated HepG2 cells either transiently or stably transfected with a nuclear receptor CAR expression vector. The PB induction mediated by CAR is regulated by a conserved 51-base pair element called PB-responsive enhancer module (PBREM) that has now been located between -1733 and -1683 bp in the gene's 5'-flanking region. An in vitro translated CAR acting as a retinoid X receptor alpha heterodimer binds directly to the two nuclear receptor sites NR1 and NR2 within PBREM. In a stably transfected HepG2 cell line, both PBREM and NR1 are activated by PB and PB-type compounds such as chlorinated pesticides, polychlorinated biphenyls and chlorpromazine. In addition to PBREM, CAR also transactivates the steroid/rifampicin-response element of the human CYP3A4 gene in HepG2 cells. Thus, activation of the repressed nuclear receptor CAR appears to be a versatile mediator that regulates PB induction of the CYP2B and other genes.

PubMed Disclaimer

Similar articles

• The nuclear orphan receptor CAR-retinoid X receptor heterodimer activates the phenobarbital-responsive enhancer module of the CYP2B gene.
  Honkakoski P, Zelko I, Sueyoshi T, Negishi M. Honkakoski P, et al. Mol Cell Biol. 1998 Oct;18(10):5652-8. doi: 10.1128/MCB.18.10.5652. Mol Cell Biol. 1998. PMID: 9742082 Free PMC article.
• A novel distal enhancer module regulated by pregnane X receptor/constitutive androstane receptor is essential for the maximal induction of CYP2B6 gene expression.
  Wang H, Faucette S, Sueyoshi T, Moore R, Ferguson S, Negishi M, LeCluyse EL. Wang H, et al. J Biol Chem. 2003 Apr 18;278(16):14146-52. doi: 10.1074/jbc.M212482200. Epub 2003 Feb 5. J Biol Chem. 2003. PMID: 12571232
• Modulation of mouse and human phenobarbital-responsive enhancer module by nuclear receptors.
  Mäkinen J, Frank C, Jyrkkärinne J, Gynther J, Carlberg C, Honkakoski P. Mäkinen J, et al. Mol Pharmacol. 2002 Aug;62(2):366-78. doi: 10.1124/mol.62.2.366. Mol Pharmacol. 2002. PMID: 12130690
• Phenobarbital response elements of cytochrome P450 genes and nuclear receptors.
  Sueyoshi T, Negishi M. Sueyoshi T, et al. Annu Rev Pharmacol Toxicol. 2001;41:123-43. doi: 10.1146/annurev.pharmtox.41.1.123. Annu Rev Pharmacol Toxicol. 2001. PMID: 11264453 Review.
• Transcriptional regulation of cytochrome p450 2B genes by nuclear receptors.
  Wang H, Negishi M. Wang H, et al. Curr Drug Metab. 2003 Dec;4(6):515-25. doi: 10.2174/1389200033489262. Curr Drug Metab. 2003. PMID: 14683479 Review.

Cited by

• CYP induction-mediated drug interactions: in vitro assessment and clinical implications.
  Lin JH. Lin JH. Pharm Res. 2006 Jun;23(6):1089-116. doi: 10.1007/s11095-006-0277-7. Epub 2006 May 26. Pharm Res. 2006. PMID: 16718615 Review.
• Liganded pregnane X receptor represses the human sulfotransferase SULT1E1 promoter through disrupting its chromatin structure.
  Kodama S, Hosseinpour F, Goldstein JA, Negishi M. Kodama S, et al. Nucleic Acids Res. 2011 Oct;39(19):8392-403. doi: 10.1093/nar/gkr458. Epub 2011 Jul 14. Nucleic Acids Res. 2011. PMID: 21764778 Free PMC article.
• Altered Gene Expression in Dioxin-Like and Non-Dioxin-Like PCB Exposed Peripheral Blood Mononuclear Cells.
  Leijs MM, Gan L, De Boever P, Esser A, Amann PM, Ziegler P, Fietkau K, Schettgen T, Kraus T, Merk HF, Baron JM. Leijs MM, et al. Int J Environ Res Public Health. 2019 Jun 13;16(12):2090. doi: 10.3390/ijerph16122090. Int J Environ Res Public Health. 2019. PMID: 31200452 Free PMC article.
• CAR requires Gadd45β to promote phenobarbital-induced mouse liver tumors in early stage.
  Hori T, Yokobori K, Moore R, Negishi M, Sueyoshi T. Hori T, et al. Front Oncol. 2023 Sep 7;13:1217847. doi: 10.3389/fonc.2023.1217847. eCollection 2023. Front Oncol. 2023. PMID: 37746289 Free PMC article.
• Species-specific regulation of PXR/CAR/ER-target genes in the mouse and rat liver elicited by o, p'-DDT.
  Kiyosawa N, Kwekel JC, Burgoon LD, Dere E, Williams KJ, Tashiro C, Chittim B, Zacharewski TR. Kiyosawa N, et al. BMC Genomics. 2008 Oct 16;9:487. doi: 10.1186/1471-2164-9-487. BMC Genomics. 2008. PMID: 18925944 Free PMC article.

MeSH terms

Substances

LinkOut - more resources

• Full Text Sources

  • Elsevier Science

• Other Literature Sources

  • The Lens - Patent Citations Database

• Molecular Biology Databases

  • BioCyc
  • Guide to Pharmacology