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)

A wide range of xenobiotic compounds are metabolized by cytochrome P450 (CYP) enzymes, and the genes that encode these enzymes are often induced in the presence of such compounds. Here, we show that the nuclear receptor CAR can recognize response elements present in the promoters of xenobiotic-responsive CYP genes, as well as other novel sites. CAR has previously been shown to be an apparently constitutive transactivator, and this constitutive activity is inhibited by androstanes acting as inverse agonists. As expected, the ability of CAR to transactivate the CYP promoter elements is blocked by the inhibitory inverse agonists. However, CAR transactivation is increased in the presence of 1,4-bis[2-(3, 5-dichloropyridyloxy)]benzene (TCPOBOP), the most potent known member of the phenobarbital-like class of CYP-inducing agents. Three independent lines of evidence demonstrate that TCPOBOP is an agonist ligand for CAR. The first is that TCPOBOP acts in a dose-dependent manner as a direct agonist to compete with the inhibitory effect of the inverse agonists. The second is that TCPOBOP acts directly to stimulate coactivator interaction with the CAR ligand binding domain, both in vitro and in vivo. The third is that mutations designed to block ligand binding block not only the inhibitory effect of the androstanes but also the stimulatory effect of TCPOBOP. Importantly, these mutations do not block the apparently constitutive transactivation by CAR, suggesting that this activity is truly ligand independent. Both its ability to target CYP genes and its activation by TCPOBOP demonstrate that CAR is a novel xenobiotic receptor that may contribute to the metabolic response to such compounds.
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PMID:The xenobiotic compound 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene is an agonist ligand for the nuclear receptor CAR. 1075 80

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

Nuclear receptors CAR and PXR play a key role in cytochrome P450 gene induction by xenobiotics. Human cytochrome P450 3A7 (CYP3A7) is expressed from early in gestation until the perinatal period, when there is a switch in expression to CYP3A4. Here we demonstrate that a PXR and CAR responsive enhancer is located approximately 8 kb upstream of the proximal CYP3A7 promoter. This distal xenobiotic responsive enhancer module (XREM) is conserved with the XREM of CYP3A4. Interestingly, not only the XREM, but also the entire promoters exhibit 90% sequence identity up to -8.8 kb, indicating a close evolutionary distance. We propose that the promoters have coevolved to functionally conserve P450 gene induction in response to xenobiotics through CAR and PXR. Thus, nuclear receptors for xenobiotics may not only play a role to provide a survival advantage during adulthood, but also to protect the embryo against endogenous and exogenous toxins.
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PMID:Functionally conserved xenobiotic responsive enhancer in cytochrome P450 3A7. 1116 90

Although CYP3A induction by dexamethasone has been extensively documented, its mechanism is still unclear because both the role of the glucocorticoid receptor and the ability of dexamethasone to activate the human pregnane X receptor have been questioned. In an attempt to resolve this problem, we investigated the response of CYP3A4 to dexamethasone (10 nm-100 microm) in primary human hepatocytes and HepG2 cells, using a variety of methods: kinetic analysis of CYP3A4 and tyrosine aminotransferase expression, effects of RU486 and cycloheximide, ligand binding assay, cotransfection of HepG2 cells with CYP3A4 reporter gene constructs and vectors expressing the glucocorticoid receptor, pregnane X receptor or constitutively activated receptor. In contrast to rifampicin (monophasic induction), dexamethasone produces a biphasic induction of CYP3A4 mRNA consisting of a low-dexamethasone component (nmol concentrations) of low amplitude (factor of 3-4) followed by a high-dexamethasone component (supramicromolar concentrations) of high amplitude (factor of 15-30). We show that the low-dexamethasone component results from the glucocorticoid receptor-mediated expression of pregnane X receptor and/or constitutively activated receptor which, in turn, are able to transactivate CYP3A4 in a xenobiotic-independent manner. At supramicromolar concentrations (>10 microm), dexamethasone binds to and activates pregnane X receptor thus producing the high-dexamethasone component of CYP3A4 induction. We conclude that, in contrast to the other xenobiotic inducers of CYP3A4, glucocorticoids play a dual role in CYP3A4 expression, first by controlling the expression of PXR and CAR under physiological conditions (submicromolar concentrations) through the classical glucocorticoid receptor pathway, and second by activating the pregnane X receptor under bolus or stress conditions (supramicromolar concentrations).
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PMID:Dual effect of dexamethasone on CYP3A4 gene expression in human hepatocytes. Sequential role of glucocorticoid receptor and pregnane X receptor. 1173 89

Cytochromes P450 (CYP)-2C enzymes fulfill an important role in xenobiotic metabolism and therefore have extensively been studied in rodents and humans. However, no CYP2C genes have been described in avian species to date. In this paper, we report the cloning, functional analysis, and regulation of chicken CYP2C45. The sequence shares up to 58% amino acid identity with CYP2Cs in other species. The overexpression of CYP2C45 in chicken hepatoma cells leghorn male hepatoma (LMH) led to increased scoparone metabolism. CYP2C45 regulation was studied in LMH cells at the mRNA level and in reporter gene assays using a construct containing 2.6 kb of its 5'-flanking region. Exposure of LMH cells to phenobarbital or metyrapone led to a 95- or 210-fold increase in CYP2C45 mRNA and a 140- or 290-fold increase in reporter gene expression, respectively. A phenobarbital response enhancer unit (PBRU) of 239 bp containing a DR-4 nuclear receptor binding site was identified within the 2.6-kb fragment. Site-specific mutation of the DR-4 revealed the requirement of this motif for CYP2C45 induction by drugs. The chicken xenobiotic receptor CXR interacted with the PBRU in electromobility shift and transactivation assays. Furthermore, the related nuclear receptors, mouse PXR and mouse CAR, transactivated this enhancer element, suggesting evolutionary conservation of nuclear receptor-DNA interactions in CYP2C induction.
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PMID:Transcriptional activation of cytochrome P450 CYP2C45 by drugs is mediated by the chicken xenobiotic receptor (CXR) interacting with a phenobarbital response enhancer unit. 1186 18

Many xenobiotics are metabolized and detoxified by cytochrome P-450s (CYP). The xenobiotics metabolizing CYPs are induced by various kinds of receptors. To induce CYP1A1, the Ah receptor requires a ligand for its activation as a transcription factor. On the other hand, benzimidazole compounds can induce CYP1A1 without binding to the Ah receptor as a ligand (ligand-independent pathway). In response to phenobarbital (PB) and other PB-type inducers, the nuclear receptor CAR (the NR-constitutive active receptor) translocates to the nucleus, forms a dimer with the retinoid X receptor (RXR), and activates the PB-responsive enhancer module (PBREM) in the PB-inducible CYP2B genes. For human CYP3A4 genes, pregnane X receptor (PXR) binds to the xenobiotic-responsive enhancer module (XREM) and upon induction by rifampicin, a PXR:RXR heterodimer could transactivate XREM.
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PMID:[Regulation of cytochrome P-450 (CYP) genes by nuclear receptors]. 1186 91

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

The products of the cytochrome P450 (CYP) genes play an important role in the detoxification of xenobiotics and environmental contaminants, and many foreign chemicals or xenobiotics can induce their expression. We have previously shown that the nuclear hormone receptor CAR (Constitutive Androstane Receptor, NR113) mediates the well studied induction of CYP2B10 gene expression by phenobarbital (PB) and 1, 4-bis-[2-(3, 5,-dichloropyridyloxy)] benzene (TCPOBOP). We have used the CAR knockout mouse model to explore the broader functions of this xenobiotic receptor. In addition to the liver, CAR is expressed in the epithelial cells of the villi in the small intestine, and this expression is required for CYP2B10 induction in response to PB and TCPOBOP in those cells. In agreement with previous observations that CAR can bind to regulatory elements in CYP3A genes, CAR is also required for induction of expression of CYP3A11 in response to both PB and TCPOBOP in liver. In males, CAR is also required for induction of liver CYP2A4 expression. In wild type animals, pretreatment with the CAR inverse agonist androstenol blocks the response of both the CYP2B10 and CYP3A11 genes to PB and TCPOBOP, and decreases basal CYP3A11 expression. CAR is also required for the response of CYP2B10 to several additional xenobiotic inducers, including chlorpromazine, clotrimazole and dieldrin, but not dexamethasone, an agonist for both the xenobiotic receptor PXR (Pregnane X Receptor NR112) and the glucocorticoid receptor. Chlorpromazine induction of CYP3A11 is also absent in CAR-deficient animals, but the responses to clotrimazole and dieldrin are retained, indicating that both of these inducers can also activate PXR (Pregnane X Receptor NR112). We conclude that CAR has broad functions in xenobiotic responses. Some are specific to CAR but others, including induction of the important drug metabolizing enzyme CYP3A, overlap with those of PXR.
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PMID:Specific and overlapping functions of the nuclear hormone receptors CAR and PXR in xenobiotic response. 1204 74

We have identified the xenobiotic receptor CAR (constitutive androstane receptor) as a key regulator of acetaminophen metabolism and hepatotoxicity. Known CAR activators as well as high doses of acetaminophen induced expression of three acetaminophen-metabolizing enzymes in wild-type but not in CAR null mice, and the CAR null mice were resistant to acetaminophen toxicity. Inhibition of CAR activity by administration of the inverse agonist ligand androstanol 1 hour after acetaminophen treatment blocked hepatotoxicity in wild type but not in CAR null mice. These results suggest an innovative therapeutic approach for treating the adverse effects of acetaminophen and potentially other hepatotoxic agents.
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PMID:Modulation of acetaminophen-induced hepatotoxicity by the xenobiotic receptor CAR. 1237 75

The systematic identification and functional analysis of human genes is revolutionizing the study of disease processes and the development and rational use of drugs. It increasingly enables medicine to make reliable assessments of the individual risk to acquire a particular disease, raises the number and specificity of drug targets and explains interindividual variation of the effectiveness and toxicity of drugs. Mutant alleles at a single gene locus for more than 20 drug metabolizing enzymes are some of the best studied individual risk factors for adverse drug reactions and xenobiotic toxicity. Increasingly, genetic polymorphisms of transporter and receptor systems are also recognized as causing interindividual variation in drug response and drug toxicity. However, pharmacogenetic and toxicogenetic factors rarely act alone; they produce a phenotype in concert with other variant genes and with environmental factors. Environmental factors may affect gene expression in many ways. For instance, numerous drugs induce their own and the metabolism of other xenobiotics by interacting with nuclear receptors such as AhR, PPAR, PXR and CAR. Genomics is providing the information and technology to analyze these complex situations to obtain individual genotypic and gene expression information to assess the risk of toxicity.
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PMID:Genomics and the prediction of xenobiotic toxicity. 1250 53


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