The Nuclear Receptors Constitutive Active/Androstane Receptor and Pregnane X Receptor Activate the<i>Cyp2c55</i>Gene in Mouse Liver

Konno, Yasuhiko; Kamino, Hiroki; Moore, Rick; Lih, Fred B.; Tomer, Kenneth B.; Zeldin, Darryl C.; Goldstein, Joyce A.; Negishi, Masahiko

doi:10.1124/dmd.110.032334

Cited by 17 publications

(14 citation statements)

References 42 publications

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“…The Cyp2c55 gene is also a CAR-regulated gene in mouse livers (Konno et al, 2010). As observed with CYP2B10 mRNA, treatment with SB 239063 also repressed an increase in CYP2C55 mRNA by phenobarbital in mouse primary hepatocytes (Fig.…”

Section: Resultsmentioning

confidence: 70%

p38 MAP Kinase Links CAR Activation and Inactivation in the Nucleus via Phosphorylation at Threonine 38

Hori

Moore

Negishi

2016

Drug Metabolism and Disposition

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Nuclear receptor constitutive androstane receptor (CAR, NR1I3), which regulates hepatic drug and energy metabolisms as well as cell growth and death, is sequestered in the cytoplasm as its inactive form phosphorylated at threonine 38. CAR activators elicit dephosphorylation, and nonphosphorylated CAR translocates into the nucleus to activate its target genes. CAR was previously found to require p38 mitogen-activated protein kinase (MAPK) to transactivate the cytochrome P450 2B (CYP2B) genes. Here we have demonstrated that p38 MAPK forms a complex with CAR, enables it to bind to the response sequence, phenobarbital-responsive enhancer module (PBREM), within the CYP2B promoter, and thus recruits RNA polymerase II to activate transcription. Subsequently, p38 MAPK elicited rephosphorylation of threonine 38 to inactivate CAR and exclude it from the nucleus. Thus, nuclear p38 MAPK exerted dual regulation by sequentially activating and inactivating CAR-mediated transcription through phosphorylation of threonine 38.

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Section: Resultsmentioning

confidence: 70%

p38 MAP Kinase Links CAR Activation and Inactivation in the Nucleus via Phosphorylation at Threonine 38

Hori

Moore

Negishi

2016

Drug Metabolism and Disposition

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“…As members of the CYP2C family have been identified as PXR and CAR targets, the expression of several CYP2C family members was investigated (van Waterschoot et al, 2009;Konno et al, 2010). Cyp2c29 was increased 2.4-fold (P = 0.040), 1.5-fold (P = 0.002), and 1.8-fold (P = 0.044) in the wild-type, Pxr-null, and hPXR mice, respectively, and in mice fed the a-tocopherol-enriched diet compared with the deficient diet.…”

Section: Resultsmentioning

confidence: 99%

“…The Cyp2c family is regulated by PXR (Cyp2c55) (van Waterschoot et al, 2009;Konno et al, 2010) and CAR in mice (Cyp2c37, Relative hepatic gene expression of Cyp2c genes by qPCR from mice fed a-tocopherol-deficient and a-tocopherol-enriched diets. All values were normalized to b-actin and expressed as fold change.…”

Section: Downloaded Frommentioning

confidence: 99%

Cytochrome P450 Regulation by α-Tocopherol in Pxr-Null and PXR-Humanized Mice

Johnson

Bonzo²,

Cheng³

et al. 2012

Drug Metab Dispos

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The pregnane X receptor (PXR) has been postulated to play a role in the metabolism of a-tocopherol owing to the up-regulation of hepatic cytochrome P450 (P450) 3A in human cell lines and murine models after a-tocopherol treatment. However, in vivo studies confirming the role of PXR in a-tocopherol metabolism in humans presents significant difficulties and has not been performed. PXR-humanized (hPXR), wildtype, and Pxr-null mouse models were used to determine whether a-tocopherol metabolism is influenced by species-specific differences in PXR function in vivo. No significant difference in the concentration of the major a-tocopherol metabolites was observed among the hPXR, wild-type, and Pxr-null mice through mass spectrometry-based metabolomics. Gene expression analysis revealed significantly increased expression of Cyp3a11 as well as several other P450s only in wild-type mice, suggesting species-specificity for a-tocopherol activation of PXR. Luciferase reporter assay confirmed activation of mouse PXR by a-tocopherol. Analysis of the Cyp2c family of genes revealed increased expression of Cyp2c29, Cyp2c37, and Cyp2c55 in wild-type, hPXR, and Pxr-null mice, which suggests PXR-independent induction of Cyp2c gene expression. This study revealed that a-tocopherol is a partial agonist of PXR and that PXR is necessary for Cyp3a induction by a-tocopherol. The implications of a novel role for a-tocopherol in Cyp2c gene regulation are also discussed.

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“…For the experiments on Cyp2b10, Cyp2c29, and Cyp2c55 expression, TCPOBOP (3 mg/kg, in corn oil, i.p.) was used as a CAR activator, 23,26) and for AhR-controlled Cyp1a2 gene expression, B(a)P (100 mg/kg, in olive oil, i.p.) was used.…”

Section: Methodsmentioning

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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The Nuclear Receptors Constitutive Active/Androstane Receptor and Pregnane X Receptor Activate theCyp2c55Gene in Mouse Liver

Cited by 17 publications

References 42 publications

p38 MAP Kinase Links CAR Activation and Inactivation in the Nucleus via Phosphorylation at Threonine 38

p38 MAP Kinase Links CAR Activation and Inactivation in the Nucleus via Phosphorylation at Threonine 38

Cytochrome P450 Regulation by α-Tocopherol in Pxr-Null and PXR-Humanized Mice

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

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