Induction of Drug Metabolism: Role for Nuclear Receptors

Handschin, Christoph

doi:10.1002/9783527623297.ch15

Cited by 106 publications

(153 citation statements)

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“…Although PXR has been recognised for its involvement in xenobiotic/drug metabolism through its role as a ligand-dependent transcription factor in the regulation of detoxifying enzymes such as CYP3A4, UGT1A1, GST and transporters (Handschin and Meyer, 2003), recent research reveals unexpected novel physiological functions, many of which seem to be rooted at its fundamental role as the sensor and effector guarding the organism against mutagenic insults from xenobiotics and endobiotics. Interestingly, in addition to reducing mutagenic DNA damages, PXR restoration inhibited cancer cell proliferation and colony formation in anchorage-independent culture.…”

Section: Discussionmentioning

confidence: 99%

“…The PXR ligands include more than 50% of clinical drugs/therapeutics, various environmental contaminants such as polyhalogenated and polycyclic aromatic hydrocarbons as well as endogenous substances such as secondary bile acids and steroids. The xenosensor and effector functions of PXR are carried out through coordinately regulating phase I, II and III detoxifying enzymes and membrane-bound transporters (Handschin and Meyer, 2003).…”

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confidence: 99%

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Pregnane X receptor suppresses proliferation and tumourigenicity of colon cancer cells

Ouyang

Eagleton

et al. 2010

Br J Cancer

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BACKGROUND: Pregnane X receptor (PXR) is a nuclear receptor that regulates the metabolism and disposition of various xenobiotics and endobioitics. We investigated a novel PXR function in regulating colon tumourigenesis in this study. METHODS: Histochemistry, transfection, cell proliferation assay, anchorage-a-dependent assay, xenograft, immunohistochemistry, immunofluorescence flow cytometry. RESULTS: Using histochemistry analysis, we found that PXR expressions were lost or greatly diminished in many colon tumours. Ectopic expression of human PXR through stable transfection of PXR into colon cancer cell line HT29 significantly inhibited cell proliferation as determined by cell proliferation assay and anchorage-independent assay. Pregnane X receptor suppressed significantly HT29 xenograft tumour growth in nude mice compared with control (310±6.2 vs 120±6 mg, Po0.01). Immunohistochemistry and immunofluorescence analysis of Ki-67 on excised xenograft tumour tissues showed that PXR inhibited cancer cell proliferation. Furthermore, expressions of PXR and Ki-67 were mutually exclusive. The flow cytometry analysis indicated that PXR caused G 0 /G 1 cell-cycle arrest. p21 WAF1/CIP1 expression was markedly elevated whereas E2F1 expression was inhibited by PXR. CONCLUSION: PXR inhibits the proliferation and tumourigenicity of colon cancer cells by controlling cell cycle at G 0 /G 1 cell phase by regulating p21 WAF1/CIP1 and E2F/Rb pathways.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Pregnane X receptor suppresses proliferation and tumourigenicity of colon cancer cells

Ouyang

Eagleton

et al. 2010

Br J Cancer

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“…CAR (constitutive androstane receptor, NR1I3) and PXR (pregnane X receptor, NR1I2) are closely related, evolutionary-conserved xenobiotic sensors of the nuclear receptor superfamily [10,11,21]. They are discussed together since they share common activators and target genes.…”

Section: Car and Pxrmentioning

confidence: 99%

From differential induction of UDP-glucuronosyltransferases in rat liver to characterization of responsible ligand-activated transcription factors, and their multilevel crosstalk in humans

Bock¹

2011

Biochemical Pharmacology

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. From differential induction of UDP-glucuronosyltransferases in rat liver to characterization of responsible ligand-activated transcription factors, and their multilevel crosstalk in humans. Biochemical Pharmacology, Elsevier, 2011, 82 (1) This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64

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“…PXR then heterodimerizes with retinoid X receptor (RXR), and the heterodimer binds to xenobiotic responsive elements (XRE) in the promoter regions of its target genes, such as Cyp3a11, to initiate their transcription. 19,22) Similarly, CAR heterodimerizes with RXR, to transcriptionally activate Cyp2b10 gene expression in response to phenobarbital and 1,4-bis-[(3,5-dichloropyridin-2-yl)oxy]-benzene (TCPOBOP). 23) In addition, the expression of Cyp1a2 genes can be induced by AhR, which dimerizes with the AhR nuclear translocator in response to many polycyclic aromatic hydrocarbons, such as benzo [a]pyrene (B(a)P).…”

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confidence: 99%

“…1) In particular, it is well known that the inducible expression of the Cyp gene is regulated by the binding of xenobiotics to nuclear receptors, such as the aryl hydrocarbon receptor (AhR), constitutive androstane receptor (CAR), and steroid and xenobiotic receptor (SXR) (the ortholog of the murine pregnane X receptor (PXR)). 18,19) For example, pregnenolone-16α-carbonitrile (PCN), a specific agonist of mouse PXR, 20,21) binds to PXR, causing its translocation from the cytoplasm to the nucleus. PXR then heterodimerizes with retinoid X receptor (RXR), and the heterodimer binds to xenobiotic responsive elements (XRE) in the promoter regions of its target genes, such as Cyp3a11, to initiate their transcription.…”

mentioning

confidence: 99%

Effect of Lipopolysaccharide on the Xenobiotic-Induced Expression and Activity of Hepatic Cytochrome P450 in Mice

Moriya

Kataoka

Fujino

et al. 2012

Biological & Pharmaceutical Bulletin

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Infection-associated inflammation can alter the expression levels and functions of cytochrome P450s (CYPs). Cyp gene expression is regulated by the activation of several nuclear receptors, including pregnane X receptor (PXR), constitutive androstane receptor (CAR), and aryl hydrocarbon receptor (AhR). These receptors can be activated by xenobiotics, including medicines. Here, to study the xenobiotic-induced fluctuations in CYP during inflammation, we examined the effect of lipopolysaccharide (LPS) treatment on the level of mRNAs encoding hepatic CYPs induced by xenobiotic-activated nuclear receptors, in mice. Both the mRNA induction of Cyp genes and the metabolic activities of CYP proteins were examined. LPS treatment caused a significant decrease in the induced expression of the mRNAs for Cyp3a11, 2c29, 2c55, and 1a2, but not for Cyp2b10. To assess the CYP enzymatic activities, CYP3A-mediated testosterone 6β-hydroxylation and the intrinsic clearance (CL int ) of nifedipine in liver microsomes were measured in mice treated with the xenobiotic pregnenolone-16alpha-carbonitrile (PCN) with or without LPS administration. Both assays revealed that the CYP3A activity, which was induced by PCN, declined significantly after LPS treatment, and this decline correlated with the Cyp3a11 mRNA level. In addition, we found that the mRNAs for interleukin (IL)-1β and tumor necrosis factor (TNF) α were increased after treatment with LPS plus xenobiotics. Our findings demonstrated that LPS treatment reduces the PXR-and AhR-mediated, and possibly CAR-mediated Cyp gene expression and further suggest that these decreases are dependent on inflammatory cytokines in the liver.

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Induction of Drug Metabolism: Role for Nuclear Receptors

Cited by 106 publications

References 120 publications

Pregnane X receptor suppresses proliferation and tumourigenicity of colon cancer cells

Pregnane X receptor suppresses proliferation and tumourigenicity of colon cancer cells

From differential induction of UDP-glucuronosyltransferases in rat liver to characterization of responsible ligand-activated transcription factors, and their multilevel crosstalk in humans

Effect of Lipopolysaccharide on the Xenobiotic-Induced Expression and Activity of Hepatic Cytochrome P450 in Mice

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