The constitutive androstane receptor (CAR) activates the expression of a reporter gene attached to the phenobarbital-response element (PBRE) of the cytochrome P450 2B1 (CYP2B1) gene in response to the barbiturate phenobarbital and the plant product picrotoxin. The xenobiotic-mediated increase in transactivation occurs in transfected primary hepatocytes and in liver transfected by biolistic-particle-mediated DNA transfer, but not in the transformed cell lines HepG2, CV-1 and HeLa, which support only constitutive activation of gene expression by CAR. Steroid co-activator 1 (SRC-1) enhances both constitutive and xenobiotic-induced CAR-mediated transactivation via the CYP2B1 PBRE in transfected primary hepatocytes. The nuclear receptor 1 (NR1) site of the PBRE is sufficient for CAR-mediated transactivation, but additional sequences within the PBRE, and hence the proteins that bind to them, are required for the interaction of CAR with SRC-1. The NR2 site of the PBRE binds proteins other than CAR, including an unidentified nuclear receptor heterodimerized with retinoid X receptor α. By binding to the proximal promoter of CYP2B1, the transcription factor Sp1 increases both basal transcription and xenobiotic-induced expression via the PBRE. Thus induction of CYP2B1 expression by xenobiotics is mediated by the nuclear receptor CAR and, for optimal expression, requires SRC-1 and Sp1.
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Research Article|
February 26 2001
Xenobiotic induction of cytochrome P450 2B1 (CYP2B1) is mediated by the orphan nuclear receptor constitutive androstane receptor (CAR) and requires steroid co-activator 1 (SRC-1) and the transcription factor Sp1
Roongsiri MUANGMOONCHAI
;
Roongsiri MUANGMOONCHAI
1
*
Department of Biochemistry and Molecular Biology, University College London, Gower Street, London WC1E 6BT, U.K.
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Despina SMIRLIS
;
Despina SMIRLIS
*
Department of Biochemistry and Molecular Biology, University College London, Gower Street, London WC1E 6BT, U.K.
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Siew-Cheng WONG
;
Siew-Cheng WONG
2
*
Department of Biochemistry and Molecular Biology, University College London, Gower Street, London WC1E 6BT, U.K.
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Mina EDWARDS
;
Mina EDWARDS
*
Department of Biochemistry and Molecular Biology, University College London, Gower Street, London WC1E 6BT, U.K.
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Ian R. PHILLIPS
;
Ian R. PHILLIPS
3
†
School of Biological Sciences, Queen Mary, University of London, Mile End Road, London E1 4NS, U.K.3
To whom correspondence should be addressed (e-mail e.shephard@ucl.ac.uk or i.r.phillips@qmw.ac.uk).
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Elizabeth A. SHEPHARD
Elizabeth A. SHEPHARD
3
*
Department of Biochemistry and Molecular Biology, University College London, Gower Street, London WC1E 6BT, U.K.3
To whom correspondence should be addressed (e-mail e.shephard@ucl.ac.uk or i.r.phillips@qmw.ac.uk).
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Biochem J (2001) 355 (1): 71-78.
Article history
Received:
October 02 2000
Revision Received:
December 15 2000
Accepted:
January 23 2001
Citation
Roongsiri MUANGMOONCHAI, Despina SMIRLIS, Siew-Cheng WONG, Mina EDWARDS, Ian R. PHILLIPS, Elizabeth A. SHEPHARD; Xenobiotic induction of cytochrome P450 2B1 (CYP2B1) is mediated by the orphan nuclear receptor constitutive androstane receptor (CAR) and requires steroid co-activator 1 (SRC-1) and the transcription factor Sp1. Biochem J 1 April 2001; 355 (1): 71–78. doi: https://doi.org/10.1042/bj3550071
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