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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.

ABSTRACT: 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 alpha. 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.

SUBMITTER: Muangmoonchai R

PROVIDER: S-EPMC1221713 | biostudies-other | 2001 Apr

REPOSITORIES: biostudies-other

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Project description:The constitutive androstane receptor (CAR) is a xenosensing nuclear receptor and regulator of cytochrome P450s (CYPs). However, the role of CAR as a basal regulator of CYP expression nor its role in sexually dimorphic responses have been thoroughly studied. We investigated basal regulation and sexually dimorphic regulation and induction by the potent CAR activator TCPOBOP and the moderate CAR activator Nonylphenol (NP). NP is an environmental estrogen and one of the most commonly found environmental toxicants in Europe and the United States. Previous studies have demonstrated that NP induces several CYPs in a sexually dimorphic manner, however the role of CAR in regulating NP-mediated sexually dimorphic P450 expression and induction has not been elucidated. Therefore, wild-type and CAR-null male and female mice were treated with honey as a carrier, NP, or TCPOBOP and CYP expression monitored by QPCR and Western blotting. CAR basally regulates the expression of Cyp2c29, Cyp2b13, and potentially Cyp2b10 as demonstrated by QPCR. Furthermore, we observed a shift in the testosterone 6alpha/15alpha-hydroxylase ratio in untreated CAR-null female mice to the male pattern, which indicates an alteration in androgen status and suggests a role for androgens as CAR inverse agonists. Xenobiotic-treatments with NP and TCPOBOP induced Cyp2b10, Cyp2c29, and Cyp3a11 in a CAR-mediated fashion; however NP only induced these CYPs in females and TCPOBOP induced these CYPs in both males and females. Interestingly, Cyp2a4, was only induced in wild-type male mice by TCPOBOP suggesting Cyp2a4 induction is not sensitive to CAR-mediated induction in females. Overall, TCPOBOP and NP show similar CYP induction profiles in females, but widely different profiles in males potentially related to lower sensitivity of males to either indirect or moderate CAR activators such as NP. In summary, CAR regulates the basal and chemically inducible expression of several sexually dimorphic xenobiotic metabolizing P450s in a manner that varies depending on the ligand.

Dataset Information

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.

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