Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0406810 (NAME)
 13,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

PBREM, the phenobarbital-responsive enhancer module of the cytochrome P-450 Cyp2b10 gene, contains two potential nuclear receptor binding sites, NR1 and NR2. Consistent with the finding that anti-retinoid X receptor (RXR) could supershift the NR1-nuclear protein complex, DNA affinity chromatography with NR1 oligonucleotides enriched the nuclear orphan receptor RXR from the hepatic nuclear extracts of phenobarbital-treated mice. In addition to RXR, the nuclear orphan receptor CAR was present in the same enriched fraction. In the phenobarbital-treated mice, the binding of both CAR and RXR was rapidly increased before the induction of CYP2B10 mRNA. In vitro-translated CAR bound to NR1, but only in the presence of similarly prepared RXR. PBREM was synergistically activated by transfection of CAR and RXR in HepG2 and HEK293 cells when the NR1 site was functional. A CAR-RXR heterodimer has thus been characterized as a trans-acting factor for the phenobarbital-inducible Cyp2b10 gene.
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PMID:The nuclear orphan receptor CAR-retinoid X receptor heterodimer activates the phenobarbital-responsive enhancer module of the CYP2B gene. 974 82

The endogenous CYP2B6 gene becomes phenobarbital (PB) inducible in androstenol-treated HepG2 cells either transiently or stably transfected with a nuclear receptor CAR expression vector. The PB induction mediated by CAR is regulated by a conserved 51-base pair element called PB-responsive enhancer module (PBREM) that has now been located between -1733 and -1683 bp in the gene's 5'-flanking region. An in vitro translated CAR acting as a retinoid X receptor alpha heterodimer binds directly to the two nuclear receptor sites NR1 and NR2 within PBREM. In a stably transfected HepG2 cell line, both PBREM and NR1 are activated by PB and PB-type compounds such as chlorinated pesticides, polychlorinated biphenyls and chlorpromazine. In addition to PBREM, CAR also transactivates the steroid/rifampicin-response element of the human CYP3A4 gene in HepG2 cells. Thus, activation of the repressed nuclear receptor CAR appears to be a versatile mediator that regulates PB induction of the CYP2B and other genes.
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PMID:The repressed nuclear receptor CAR responds to phenobarbital in activating the human CYP2B6 gene. 1003 83

The biochemistry of foreign compound metabolism and the roles played by individual cytochrome P450 (CYP) enzymes in drug metabolism and in the toxification and detoxification of xenochemicals prevalent in the environment are important areas of molecular pharmacology and toxicology that have been widely studied over the past decade. Important advances in our understanding of the mechanisms through which foreign chemicals impact on these P450-dependent metabolic processes have been made during the past 2 years with several key discoveries relating to the mechanisms through which xenochemicals induce the expression of hepatic P450 enzymes. Roles for three "orphan" nuclear receptor superfamily members, designated CAR, PXR, and PPAR, in respectively mediating the induction of hepatic P450s belonging to families CYP2, CYP3, and CYP4 in response to the prototypical inducers phenobarbital (CAR), pregnenolone 16alpha-carbonitrile and rifampicin (PXR), and clofibric acid (PPAR) have now been established. Two other nuclear receptors, designated LXR and FXR, which are respectively activated by oxysterols and bile acids, also play a role in liver P450 expression, in this case regulation of P450 cholesterol 7alpha-hydroxylase, a key enzyme of bile acid biosynthesis. All five P450-regulatory nuclear receptors belong to the same nuclear receptor gene family (family NR1), share a common heterodimerization partner, retinoid X-receptor (RXR), and are subject to cross-talk interactions with other nuclear receptors and with a broad range of other intracellular signaling pathways, including those activated by certain cytokines and growth factors. Endogenous ligands of each of those nuclear receptors have been identified and physiological receptor functions are emerging, leading to the proposal that these receptors may primarily serve to modulate hepatic P450 activity in response to endogenous dietary or hormonal stimuli. Accordingly, P450 induction by xenobiotics may in some cases lead to a perturbation of endogenous regulatory circuits with associated pathophysiological consequences.
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PMID:P450 gene induction by structurally diverse xenochemicals: central role of nuclear receptors CAR, PXR, and PPAR. 1046 36

The nuclear orphan receptor CAR (constitutively active receptor or constitutive androstane receptor) can be activated in response to xenochemical exposure, such as activation by phenobarbital of a response element called NR1 found in the CYP2B gene. Here various steroids were screened for potential endogenous chemicals that may activate CAR, using the NR1 enhancer and Cyp2b10 induction in transfected HepG2 cell and/or in mouse primary hepatocytes as the experimental criteria. 17beta-Estradiol and estrone activated NR1, whereas estriol, estetrol, estradiol sulfate, and the synthetic estrogen diethylstilbestrol did not. On the other hand, progesterone and androgens repressed NR1 activity in HepG2 cells, and the repressed NR1 activity was fully restored by estradiol. Moreover, estrogen treatment elicited nuclear accumulation of CAR in the mouse livers, as well as primary hepatocytes, and induced the endogenous Cyp2b10 gene. Ovariectomy did not affect either the basal or induced level of CAR in the nucleus of the female livers, while castration slightly increased the basal and greatly increased the induced levels in the liver nucleus of male mice. Thus, endogenous estrogen appears not to regulate CAR in female mice, whereas endogenous androgen may be the repressive factor in male mice. Estrogen at pharmacological levels is an effective activator of CAR in both female and male mice, suggesting a biological and/or toxicological role of this receptor in estrogen metabolism. In addition to mouse CAR, estrogens activated rat CAR, whereas human CAR did not respond well to the estrogens under the experimental conditions.
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PMID:Estrogen activation of the nuclear orphan receptor CAR (constitutive active receptor) in induction of the mouse Cyp2b10 gene. 1107 20

The barbiturate phenobarbital induces the transcription of cytochromes P450 (CYPs) 2B through the constitutive androstane receptor (CAR; NR1I3). CAR is a member of the nuclear receptor family (NR1) mostly expressed in the liver, which heterodimerizes with retinoid X receptor (RXR) and was shown to transactivate both the phenobarbital responsive element module of the human CYP2B6 gene and the CYP3A4 xenobiotic response element. Because previous studies in rodent hepatocyte cultures have shown that the phenobarbital-mediated induction of CYP2B genes is potentiated by glucocorticoids, we examined the role of activated glucocorticoid receptor in this process. We show that submicromolar concentrations of dexamethasone enhance phenobarbital-mediated induction of CYP3A4, CYP2B6, and CYP2C8 mRNA in cultured human hepatocytes. In parallel, we observed that glucocorticoid agonists, such as dexamethasone, prednisolone, or hydrocortisone, specifically increase human car (hCAR) mRNA expression. Accumulation of hCAR mRNA parallels that of tyrosine aminotransferase: both mRNAs reach a maximum at a concentration of 100 nM dexamethasone and are down-regulated by concomitant treatment with the glucocorticoid antagonist RU486. Moreover, the effect of dexamethasone on hCAR mRNA accumulation appears to be of transcriptional origin because the addition of protein synthesis inhibitor cycloheximide has no effect, and dexamethasone does not affect the degradation of hCAR mRNA. Furthermore, dexamethasone increases both basal and phenobarbital-mediated nuclear translocation of CAR immunoreactive protein in human hepatocytes. The up-regulation of CAR mRNA and protein in response to dexamethasone explains the synergistic effect of this glucocorticoid on phenobarbital-mediated induction of CYP2B genes and the controversial role of the glucocorticoid receptor on phenobarbital-mediated CYP gene inductions.
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PMID:Dexamethasone enhances constitutive androstane receptor expression in human hepatocytes: consequences on cytochrome P450 gene regulation. 1109 84

The present study compares the sensitivity to chronic exposure to glutamate agonists of SMI-32-positive rat-derived embryonic motoneurons under both mixed neuron/glia and purified cultures. We found that in spite of a trophic role of glia on cultured motoneurons, SMI-32-positive cells are more sensitive to excitotoxicity in the presence of glia than in purified culture, very likely through nitric oxide released by non-neuronal cells. The rank order of potency for inducing toxicity after 48 h incubation was AMPA>kainate>NMDA, with EC(50): 0.43, 4.9 and 49 microM, respectively, in mixed neuron/glia culture and 14, 32 and 135 microM in purified cultures. The effect of NMDA was dose-dependently potentiated by glycine, with similar potency in the two culture conditions. The effect of agonists was completely antagonized by the specific antagonists CNQX, BNQX and MK801 in both culture conditions. Motoneurons were similarly immunoreactive to NR1 and GluR2 antibodies under both mixed neuron/glia and purified cultures, thus confirming the presence of the calcium-impermeant AMPA receptor subtypes and of the obligatory subunit for NMDA receptors. The effect of kainate in mixed neuron/glia culture was reduced by the addition of 40 microM N-nitro-L-arginine or L-NAME, which shifted the EC(50) to 9 microM. By contrast, L-NAME did not modify the effect of kainic acid in purified cultures. These results suggest that the release of nitric oxide by non-neuronal cells in culture enhances glutamate excitotoxicity in SMI-32-positive cells, and that direct activation of ionotropic glutamate receptors is not enough to explain the mechanism of chronic motoneuron degeneration occurring in vivo in amyotrophic lateral sclerosis (ALS).
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PMID:Nitric oxide produced by non-motoneuron cells enhances rat embryonic motoneuron sensitivity to excitotoxins: comparison in mixed neuron/glia or purified cultures. 1170 Nov 54

In contrast to the well-known Ah receptor-mediated regulation of the CYP1A1 gene by polycyclic aromatic hydrocarbons, the molecular mechanism by which phenobarbital (PB) and PB-like inducers affect transcription of CYP genes remains unknown; no receptor for these chemicals has been found to date. However, in the last 5 years PB-responsive sequences have been identified in the 5' flanking regions of several P450 genes. The phenobarbital-responsive enhancer unit (PBRU) of CYP2B gene family members contain two potential nuclear receptor binding sites (NR1 and NR2) that flank a nuclear factor 1 (NF-1) binding motif. The nuclear factors that regulate PBRU activity have not yet been characterized. It seems that PB may activate multiple nuclear orphan receptors to induce various CYP genes. CYP2B and CYP3A genes appear to be targets for the orphan receptors CAR and PXR, respectively. It is also possible that the pleiotropic effects of PB can, in part, be explained by the ability of the CAR-RXR heterodimer to bind to a variety of nuclear receptor binding motifs. The induction of cytochromes P450 may result in interactions between xenobiotics and in the interference of xenobiotic metabolism and endogenous signalling pathways.
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PMID:Phenobarbital-induced expression of cytochrome P450 genes. 1199 99

In order to delineate mechanisms of noise-induced hearing loss, we assessed noise trauma and its pharmacological modulation in the guinea pig. Auditory threshold shifts (measured by auditory brainstem responses), hair cell loss and lipid peroxidation (8-isoprostane formation) were determined in the absence or presence of agents known to influence the formation or action of reactive oxygen species (ROS): the non-specific N-methyl-D-aspartate (NMDA) receptor antagonist (+)-MK-801, its inactive isomer (-)-MK-801, the selective NR1/2B NMDA receptor antagonist PD 174494, the nitric oxide synthase (NOS) inhibitor L-N(omega)-Nitroarginine methyl ester (L-NAME) and the anti-oxidant N-acetylcysteine (NAC). (+)-MK-801 and NAC attenuated threshold shifts and hair cell loss effectively while PD 174494 did so partially. L-NAME attenuated threshold shifts at 2 kHz but increased them at 20 kHz, and (-)-MK-801 was ineffective. Noise-induced elevation in 8-isoprostane in the cochlea was significantly attenuated by (+)-MK-801 and PD 174494 in the organ of Corti and modiolar core, by L-NAME in the lateral wall and modiolar core, and by NAC in all three regions. (-)-MK-801 did not influence noise-induced 8-isoprostane formation. There was a significant correlation between threshold shifts at 4 kHz, hair cell loss and the level of 8-isoprostane formed in the organ of Corti, but not in the lateral wall tissues. This finding suggests a causal relationship between ROS formation and functional and morphological damage. NMDA receptors and, to some extent, NOS may be involved in noise-induced ROS formation. The data also indicate that lipid peroxidation in the lateral wall tissues does not influence permanent threshold shifts.
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PMID:Protection from noise-induced lipid peroxidation and hair cell loss in the cochlea. 1261 49

The expression of the CAR gene and inducibility of CYP2B protein in the liver of male Wistar rats treated with phenobarbital (PB) and triphenyldioxane (TPD) were investigated. To clarify the role of phosphorylation/dephosphorylation in these processes, rats were treated with inhibitors of Ca(2+)/calmodulin-dependent kinase II (W7) or protein phosphatases PP1 and PP2A (OA) before induction. Constitutive expression of the CAR gene in livers of untreated rats was detected by multiplex RT-PCR. Treatment with W7 resulted in a 2.8-fold induction of CAR gene expression, whereas OA led to a 2.4-fold decrease of the mRNA level. The same results were obtained for CYP2B genes expression, which were increased by W7 treatment (two-fold) and decreased by OA (2.3-fold). PB-induction did not lead to significant alteration in the level of CAR gene expression, although CYP2B genes expression was enhanced two-fold over control values. TPD caused a two-fold increase of both CAR and CYP2B mRNA levels. Both inducers reduced the effects of inhibitors on CAR gene expression. Results of EMSA showed that PB, TPD or W7 alone induced formation of complexes of NR1 with nuclear proteins. Appearance of the complexes correlated with an increase in CYP2B expression, and their intensities were modulated by the protein kinase inhibitors. Thus, our results demonstrate that constitutive expressions of CAR as well as CYP2B during induction are regulated by phosphorylation/dephosphorylation processes.
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PMID:CAR expression and inducibility of CYP2B genes in liver of rats treated with PB-like inducers. 1615 63

Activation of the neuronal-glial network in the spinal cord dorsal horn (SCDH) mediates various chronic painful conditions. We studied spinal neuronal-astrocyte signaling interactions involved in the maintenance of painful diabetic neuropathy (PDN) in type 2 diabetes. We used the db/db mouse, an animal model for PDN of type 2 diabetes, which develops mechanical allodynia from 6 to 12 wk of age. In this study, enhanced substance P expression was detected in the presynaptic sensory fibers innervating lamina I-III in the lumbar SCDH (LSCDH) of the db/db mouse at 10 wk of age. This phenomenon is associated with enhanced spinal ERK1/2 phosphorylation in projection sensory neurons and regional astrocyte activation. In addition, peak phosphorylation of the NR1 subunit of N-methyl-D-aspartate receptor (NMDAR), along with upregulation of neuronal and inducible nitric oxide synthase (nNOS and iNOS) expression were detected in diabetic mice. Expression of nNOS and iNOS was detected in both interneurons and astrocytes in lamina I-III of the LSCDH. Treatment with MK801, an NMDAR inhibitor, inhibited mechanical allodynia, ERK1/2 phosphorylation, and nNOS and iNOS upregulation in diabetic mice. MK801 also reduced astrocytosis and glial acidic fibrillary protein upregulation in db/db mice. In addition, N(G)-nitro-L-arginine methyl ester (L-NAME), a nonspecific NOS inhibitor, had similar effects on NMDAR signaling and NOS expression. These results suggest that nitric oxide from surrounding interneurons and astrocytes interacts with NMDAR-dependent signaling in the projection neurons of the SCDH during the maintenance of PDN.
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PMID:Neuron-astrocyte signaling network in spinal cord dorsal horn mediates painful neuropathy of type 2 diabetes. 2257 63


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