The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity

Staudinger, Jeff; Goodwin, Bryan; Jones, Stacey A.; Hawkins-Brown, Diane; MacKenzie, Kathleen I.; Latour, Anne M.; Liu, Yaping; Klaassen, Curtis D.; Brown, Kathleen K.; Reinhard, John F.; Willson, Timothy M.; Koller, Beverly H.; Kliewer, Steven A.

doi:10.1073/pnas.051551698

Cited by 1,218 publications

(1,156 citation statements)

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“…We show that SQ1 potently induces both CYPs and shares signalling pathways with the PB regulation of these genes. Moreover, we discovered that bile acids also induce CYP2H1 and confirm recent data in mammals that bile acids regulate CYP3A (17,18). Cell culture conditions and transfection: LMH cells were cultured and transfected as described previously (7).…”

Section: Introductionsupporting

confidence: 81%

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A Link between Cholesterol Levels and Phenobarbital Induction of Cytochromes P450

Ourlin

Handschin

Kaufmann

et al. 2002

Biochemical and Biophysical Research Communications

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Squalestatin1 (SQ1), a potent inhibitor of squalene synthase produced a dose-dependent induction of cytochromes P450 CYP2H1 and CYP3A37 mRNAs in chicken hepatoma cells. The effect of SQ1 was completely reversed by 25-hydroxycholesterol. Bile acids elicited an induction of CYP3A37 and CYP2H1 mRNA. Bile acids also reduced the phenobarbital induction of CYP2H1 but not of CYP3A37 mRNA. The effects of SQ1 and its reversal by 25-hydroxycholesterol and the effects of bile acids were reproduced in reporter gene assays with a phenobarbital-responsive enhancer unit of CYP2H1. These data suggest that an endogenous molecule related to cholesterol homeostasis regulates induction of drug-inducible CYPs.

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Section: Introductionsupporting

confidence: 81%

“…CYP3A4 are induced by bile acids (17,18). Primary bile acids are major products of cholesterol catabolism, synthesised specifically in the hepatocyte (21).…”

Section: Discussionmentioning

confidence: 99%

A Link between Cholesterol Levels and Phenobarbital Induction of Cytochromes P450

Ourlin

Handschin

Kaufmann

et al. 2002

Biochemical and Biophysical Research Communications

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“…Certain bile acids (e.g. lithocholic acid) have been shown to directly activate PXR at concentrations between 10-100 M [50,51]. Moreover, three bile acid precursors (7-hydroxy-4-cholesten-3-one, 5-cholestan-3,7,12-triol, and 4-cholesten-3-one) activate mouse PXR in the low -8 -micromolar range but are less potent activators of its human ortholog [52].…”

Section: Car and Pxr Confer Hepatoprotection Upon Bile Acid Exposurementioning

confidence: 99%

“…However, the xenosensors also increase alternate, compensatory pathways for lowering hepatic bile acid levels by inducing their hydroxylation, conjugation and subsequent excretion via blood and urine [50,51,54,55,83]. In contrast, FXR is predominantly responsible for triggering bile acid export from the liver into the bile duct followed by excretion of -12 -bile acids via feces [84,85].…”

Section: Nuclear Receptor Regulation Of Cholesterol Biosynthesis Andmentioning

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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“…For example, CYP3A4, the predominant human hepatic P450, metabolizes greater than 60% of pharmaceutical agents (Sonoda and Evans, 2003). Other P450s such as CYP2D6, CYP2B6, CYP2C9, and CYP1A2 are also important in xenobiotic metabolism, as well as steroid catabolism, bile acid metabolism, and bilirubin elimination (Namkung et al, 1988;Baldwin and LeBlanc, 1992;Schuetz et al, 2001;Staudinger et al, 2001b). NP has been shown to induce several P450s in rodents in vivo, including Cyp2b and Cyp3a subfamily members.…”

Section: Introductionmentioning

confidence: 99%

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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The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity

Cited by 1,218 publications

References 41 publications

A Link between Cholesterol Levels and Phenobarbital Induction of Cytochromes P450

A Link between Cholesterol Levels and Phenobarbital Induction of Cytochromes P450

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

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

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