Specific and overlapping functions of the nuclear hormone receptors CAR and PXR in xenobiotic response

Wei, Ping; Zhang, J; Dowhan, Dennis H.; Han, Yushui; Moore, David D.

doi:10.1038/sj.tpj.6500087

Cited by 228 publications

(179 citation statements)

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“…1). Previous data have demonstrated that the potent CAR agonist TCPOBOP only induces Cyp2a4 in males and in a CAR-dependent fashion (Wei et al, 2002). Statistically significant increases in Cyp2a were not observed by Western blotting or testosterone 6α-hydroxylase activity in males.…”

Section: Discussionmentioning

confidence: 75%

“…Dexamethasone downregulates the female-predominant Cyp3a41 in a PXR-dependent manner, while male mice did not demonstrate downregulation of any Cyp3a subfamily members (Anakk et al, 2004). In addition, the CAR activators, phenobarbital and 1,4-bis-[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) demonstrate male-specific Cyp2a4 induction (Wei et al, 2002). Lastly, St. John's wort mediated induction of CYP3A4 is greater in human females than males (Gurley et al, 2002).…”

Section: Introductionmentioning

confidence: 91%

“…Recently, induction of Cyp2a, Cyp2b, and Cyp3a subfamily members was shown to be regulated by PXR and its relative, the constitutive androstane receptor (CAR), in a sexually dimorphic manner (Sierra-Santoyo et al, 2000;Wei et al, 2002;Anakk et al, 2004;Nelson et al, 2005). For example, PXR-null male mice demonstrate greater Cyp3a activity, while PXRnull female mice demonstrate reduced Cyp3a activity compared to same-sex wild-type mice (Anakk et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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Gender-specific induction of cytochrome P450s in nonylphenol-treated FVB/NJ mice

Hernández

Chapman

Kretschmer

et al. 2006

Toxicology and Applied Pharmacology

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Nonylphenol (NP) is a breakdown product of nonylphenol ethoxylates, which are used in a variety of industrial, agricultural, household cleaning, and beauty products. NP is one of the most commonly found toxicants in the United States and Europe and is considered a toxicant of concern because of its long half-life. NP is an environmental estrogen that also activates the pregnane X-receptor (PXR) and in turn induces P450s. No study to date has examined the gender-specific effects of NP on hepatic P450 expression. We provided NP at 0, 50 or 75 mg/kg/day for 7 days to male and female FVB/NJ mice and compared their P450 expression profiles. Q-PCR was performed on hepatic cDNA using primers to several CYP isoforms regulated by PXR or its relative, the constitutive androstane receptor (CAR). In female mice, NP induced Cyp2b10 and Cyp2b13, and downregulated the female-specific P450s, Cyp3a41 and Cyp3a44. In contrast, male mice treated with NP showed increased expression of Cyp2a4, Cyp2b9, and Cyp2b10. Western blots confirmed induction of Cyp2b subfamily members in both males and females. Consistent with the Q-PCR data, Western blots showed dose-dependent downregulation of Cyp3a only in females and induction of Cyp2a only in males. The overall increase in female-predominant P450s in males (Cyp2a4, 2b9) and the decrease in female-predominant P450s in females (Cyp3a41, 3a44) suggest that NP is in part feminizing the P450 profile in males and masculinizing the P450 profile in females. Testosterone hydroxylation was also altered in a genderspecific manner, as testosterone 16α-hydroxylase activity was only induced in NP-treated males. In contrast, NP-treated females demonstrated a greater propensity for metabolizing zoxazolamine probably due to greater Cyp2b induction in females. In conclusion, NP causes gender-specific P450 induction and therefore exposure to NP may cause distinct pharmacological and toxicological effects in males compared to females.

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Section: Discussionmentioning

confidence: 75%

Section: Introductionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

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Gender-specific induction of cytochrome P450s in nonylphenol-treated FVB/NJ mice

Hernández

Chapman

Kretschmer

et al. 2006

Toxicology and Applied Pharmacology

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“…Mice with genetic ablations of CAR and PXR have significantly reduced inducibility of CYPs by a variety of drugs [8,9]. Whereas these two receptors share some common ligands and also have an overlapping target gene pattern [10][11][12][13], the mode of activation for CAR and PXR is quite different [14]. PXR is located in the nucleus, it has a low basal activity and is highly activated upon ligand binding [14,15].…”

Section: Introductionmentioning

confidence: 99%

Regulatory network of lipid-sensing nuclear receptors: roles for CAR, PXR, LXR, and FXR

Handschin¹,

Meyer²

2005

Archives of Biochemistry and Biophysics

156

105

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Cloning and characterization of the orphan nuclear receptors constitutive androstane receptor (CAR, NR1I3) and pregnane X receptor (PXR, NR1I2) led to major breakthroughs in studying drug-mediated transcriptional induction of drugmetabolizing cytochromes P450 (CYP). More recently, additional roles for CAR and PXR have been discovered. As examples, these xenosensors are involved in the homeostasis of cholesterol, bile acids, bilirubin and other endogenous hydrophobic molecules in the liver: CAR and PXR thus form an intricate regulatory network with other members of the nuclear receptor superfamily, foremost the cholesterol-sensing liver X receptor (LXR, NR1H2/3) and the bileacid-activated farnesoid X receptor (FXR, NR1H4). In this review, functional interactions between these nuclear receptors as well as the consequences on physiology and pathophysiology of the liver are discussed.Key Words: nuclear receptors; drug-induction; lipids; bile acids; cholesterol; CAR; PXR; LXR; FXR; cytochrome P450 -4 -Metabolism of drugs and other xenobiotics in the liver is our body's primary defense against accumulation of potentially toxic, lipophilic compounds. The superfamily of cytochromes P450 (CYPs) are the best-studied class of enzymes in this task [1]. Transcriptional and post-transcriptional regulation of CYPs after exposure to certain drugs or other xenobiotics has been described several decades ago. Classically, the barbiturate phenobarbital induces its own metabolism and excretion by elevating CYP levels [2]. However, the molecular mechanisms underlying this observation remained a conundrum until the discovery and subsequent characterization of the constitutive androstane receptor (CAR, official nomenclature NR1I3) and the pregnane X receptor (PXR, NR1I2, alternatively called PAR or SXR), two members of the superfamily of nuclear receptors [3][4][5][6][7]. Mice with genetic ablations of CAR and PXR have significantly reduced inducibility of CYPs by a variety of drugs [8,9]. Whereas these two receptors share some common ligands and also have an overlapping target gene pattern [10][11][12][13], the mode of activation for CAR and PXR is quite different [14]. PXR is located in the nucleus, it has a low basal activity and is highly activated upon ligand binding [14,15]. In contrast, in the non-induced state, CAR resides in the cytoplasm. After treatment with activators such as phenobarbital, CAR shuttles to the nucleus to activate its target genes. Moreover, CAR localization and activity is regulated by various protein phosphorylation events [16][17][18]. For a more detailed discussion of CAR and PXR functions in drug-mediated induction of CYPs, see some recent reviews (e.g. refs. [19-23] and references therein).-5 - The nuclear receptor NR1I group includes xenosensors and lipid-sensing membersCompounds that induce transcription of CYPs and that activate CAR and PXR are structurally very diverse [21]. However, most of them are small in size and are highly lipophilic [24]. Whereas the CAR ligand-binding domain stru...

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“…[10][11][12] In mice that are deficient in either of these genes, they have clear, select and impressively debilitated capabilities of detoxifying xenobiotics and endobiotics. [13][14][15] This is most evident in the regulation of the central P 450 detoxifying enzyme Cyp3a4 (Cyp3a11 in mice), which is strongly activated by both CAR and PXR ligands, and reduced in activity in CAR Ϫ/Ϫ and PXR Ϫ/Ϫ mice. Moreover, these two NRs are critical to the handling of bile acids, notably lithocholic acid.…”

mentioning

confidence: 99%

Exercising the nuclear option to treat cholestasis: CAR and PXR ligands

Karpen

2005

Hepatology

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Specific and overlapping functions of the nuclear hormone receptors CAR and PXR in xenobiotic response

Cited by 228 publications

References 30 publications

Gender-specific induction of cytochrome P450s in nonylphenol-treated FVB/NJ mice

Gender-specific induction of cytochrome P450s in nonylphenol-treated FVB/NJ mice

Regulatory network of lipid-sensing nuclear receptors: roles for CAR, PXR, LXR, and FXR

Exercising the nuclear option to treat cholestasis: CAR and PXR ligands

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