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)

The cytochrome P450 gene CYP2H1 is highly induced by phenobarbital in chick embryo hepatocytes. Recent studies have established that the orphan nuclear receptor CAR plays a critical role in the induction mechanism. Here, we show that a high concentration of the potent glucocorticoid and progesterone receptor antagonist RU486 almost completely blocks phenobarbital-induced accumulation of CYP2H1 mRNA in hepatocytes yet has no effect on basal expression. In marked contrast, CYP2H1 mRNA induced by the phenobarbital-type inducers glutethimide and 2-allylisopropylacetamide is not affected by RU486. RU486 inhibition is not mediated through the glucocorticoid or progesterone receptors. Transient transfection studies showed that RU486 does not repress through activation of the orphan receptor PXR and subsequent competition with CAR for binding to the upstream drug-responsive 556-base-pair enhancer. Additionally, none of the known functional transcription factor binding sites found in the enhancer region was a target of RU486 inhibition. Using an artificial construct containing multiple CAR binding sites, we also established that RU486 has no direct effect on the activity of exogenously expressed CAR. There is no evidence that phenobarbital binds to CAR; we propose that RU486 inhibits phenobarbital induction, either by interfering with a phenobarbital-dependent mechanism responsible for nuclear import of CAR or with the metabolism of phenobarbital to the true inducer. Whether a novel nuclear receptor that binds RU486 at high concentrations plays a role in the inhibitory action of RU486 is an interesting possibility.
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PMID:The antiglucocorticoid RU486 inhibits phenobarbital induction of the chicken CYP2H1 gene in primary hepatocytes. 1145 14

The drug metabolizing enzyme cytochrome P450 3A4 (CYP3A4) is thought to be involved in the metabolism of nearly 50% of all the drugs currently prescribed. Alteration in the activity or expression of this enzyme seems to be a key predictor of drug responsiveness and toxicity. Currently available studies indicate that the ligand-activated nuclear receptors pregnane X receptor (PXR; NR1I2) and constitutive androstane receptor (CAR; NR1I3) regulate CYP3A4 expression. However, in cell-based reporter assays, CYP3A4 promoter activity was most pronounced in liver-derived cells and minimal or modest in non-hepatic cells, indicating that a liver-specific factor is required for physiological transcriptional response. Here we show that the orphan nuclear receptor hepatocyte nuclear factor-4alpha (HNF4alpha; HNF4A) is critically involved in the PXR- and CAR-mediated transcriptional activation of CYP3A4. We identified a specific cis-acting element in the CYP3A4 gene enhancer that confers HNF4alpha binding and thereby permits PXR- and CAR-mediated gene activation. Fetal mice with conditional deletion of Hnf4alpha had reduced or absent expression of CYP3A. Furthermore, adult mice with conditional hepatic deletion of Hnf4alpha had reduced basal and inducible expression of CYP3A. These data identify HNF4alpha as an important regulator of coordinate nuclear-receptor-mediated response to xenobiotics.
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PMID:The orphan nuclear receptor HNF4alpha determines PXR- and CAR-mediated xenobiotic induction of CYP3A4. 1251 43

This review summarizes recent findings indicating that members of the orphan nuclear receptor superfamily regulate the synthesis of their CYP genes which code CYP enzymes involved in metabolism of endogenous and exogenous compounds. The foreign compounds metabolism and the role played by individual cytochrome P450 (CYP) enzymes in the activation and detoxification of xenochemicals prevalent in the environment are important areas of molecular pharmacology and toxicology. The advances in our understanding of the mechanisms through which foreign chemicals impact on these CYP-dependent metabolic processes have been made during the past years. Role for three "orphan" nuclear receptor superfamily members, designated CAR (constitutive androstane receptor), PXR/SXR (pregnelone X receptor) and PPAR (peroxisome proliferator activated receptor), in respectively mediating the induction of hepatic CYPs belonging to families CYP2, CYP3, and CYP4 has now been established. The CYP gene products such as CYP3A, CYP2B and PPAR are essential for metabolism of endogenous steroid hormones, fatty acids and various xenobiotics including drugs. Unexpectedly, it has been shown that SXR, which regulates CYP3A, can also regulate CYP2B via recognition of the phenobarbital response element (PBRE). In a type of functionally symmetry, orphan receptor CAR was found to activate CYP3A through SXR/PXR response element. Indeed, SXR/PXR binds to inverted (IR-6) and direct (DR-4) response element localized to regulatory DNA regions of human CYP3A4 and rat CYP3A23 genes, respectively. These observations provide a rational explanation for the activation of multiple CYP gene classes by certain xenobiotics as well as the propensity for drug-drug interactions. In addition, both endogenous and exogenous ligands which act as activators of nuclear receptors can result in disruption of cellular homeostasis.
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PMID:[The role of nuclear receptors in cytochrome P-450 induction by xenochemicals]. 1266 59

The orphan nuclear receptor CAR (NR1I3) has been characterized as a central component in the coordinate response to xenobiotic and endobiotic stress. In this study, we demonstrate that CAR plays a pivotal function in energy homeostasis and establish an unanticipated metabolic role for this nuclear receptor. Wild-type mice treated with the synthetic CAR agonist 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) exhibited decreased serum concentration of the thyroid hormone (TH) thyroxine (T(4)). However, treatment of Car(-/-) mice with TCPOBOP failed to elicit these changes. To examine whether CAR played a role in the regulation of TH levels under physiological conditions, wild-type and Car(-/-) mice were fasted for 24 h, a process known to alter TH metabolism in mammals. As expected, the serum triiodothyronine and T(4) concentrations decreased in wild-type mice. However, triiodothyronine and T(4) levels in fasted Car(-/-) mice remained significantly higher than those in fasted wild-type animals. Concomitant with the changes in serum TH levels, both CAR agonist treatment and fasting induced the expression of CAR target genes (notably, Cyp2b10, Ugt1a1, Sultn, Sult1a1, and Sult2a1) in a receptor-dependent manner. Importantly, the Ugt1a1, Sultn, Sult1a1, and Sult2a1 genes encode enzymes that are capable of metabolizing TH. An attenuated reduction in TH levels during fasting, as observed in Car(-/-) mice, would be predicted to increase weight loss during caloric restriction. Indeed, when Car(-/-) animals were placed on a 40% caloric restriction diet for 12 weeks, Car(-/-) animals lost over twice as much weight as their wild-type littermates. Thus, CAR participates in the molecular mechanisms contributing to homeostatic resistance to weight loss. These data imply that CAR represents a novel therapeutic target to uncouple metabolic rate from food intake and has implications in obesity and its associated disorders.
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PMID:The nuclear receptor CAR is a regulator of thyroid hormone metabolism during caloric restriction. 1500 31

The human constitutive androstane receptor (CAR, NR1I3) is a member of the orphan nuclear receptor superfamily that plays an important role in the control of drug metabolism and disposition. In this study, we sequenced all the coding exons of the NR1I3 gene for 334 Japanese subjects. We identified three novel single nucleotide polymorphisms (SNPs) that induce non-synonymous alterations of amino acids (His246Arg, Leu308Pro, and Asn323Ser) residing in the ligand-binding domain of CAR, in addition to the Val133Gly variant, which was another CAR variant identified in our previous study. We performed functional analysis of these four naturally occurring CAR variants in COS-7 cells using a CYP3A4 promoter/enhancer reporter gene that includes the CAR responsive elements. The His246Arg variant caused marked reductions in both transactivation of the reporter gene and in the response to 6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime (CITCO), which is a human CAR-specific agonist. The transactivation ability of the Leu308Pro variant was also significantly decreased, but its responsiveness to CITCO was not abrogated. The transactivation ability and CITCO response of the Val133Gly and Asn323Ser variants did not change as compared to the wild-type CAR. These data suggest that the His246Arg and Leu308Pro variants, especially His246Arg, may influence the expression of drug-metabolizing enzymes and transporters that are transactivated by CAR.
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PMID:Functional analysis of four naturally occurring variants of human constitutive androstane receptor. 1599 Mar 49