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

Pregnane X receptor (PXR, NR1I2) and constitutive androstane receptor (CAR, NR1I3) are the principal regulators of drug/xenobiotic disposition and toxicity. These nuclear receptors display considerable cross-regulation of their target genes, and species-specific, yet promiscuous activation by a large number of structurally dissimilar ligands. Activation of PXR and/or CAR will frequently result in enhanced drug metabolism, disturbances in homeostasis of endogenous substances, and increased toxicity. Thus, understanding, measurement and prediction of ligand-elicited activation of PXR and CAR receptors is of utmost importance for the drug development process. In this mini-review, we will review the recent elucidation of structural properties of PXR and CAR, the molecular determinants of their ligand and species specificities and progress made in in silico models for identification of PXR and CAR activators.
 ...
PMID:Ligand recognition by drug-activated nuclear receptors PXR and CAR: structural, site-directed mutagenesis and molecular modeling studies. 1691 99

Both the human pregnane X receptor (hPXR) and constitutive androstane receptor (hCAR) are capable of regulating CYP3A4 and CYP2B6 gene expression. However, the majority of currently identified CYP3A4 and CYP2B6 inducers are confirmed activators of hPXR but not hCAR. To compare these receptors with respect to their chemical selectivities, 16 drugs known to induce CYP3A4 and/or CYP2B expression were evaluated for relative activation of hPXR versus hCAR. Because of the high basal but low chemical-induced activation of hCAR in immortalized cells, alternative methods were used to evaluate hCAR activation potential. Thirteen of the 16 compounds were classified as moderate to strong hPXR activators. In contrast, carbamazepine (CMZ), efavirenz (EFV), and nevirapine (NVP) were classified as negligible or weak hPXR activators at concentrations associated with efficacious CYP2B6 reporter or endogenous gene induction in primary human hepatocytes, suggesting potential activation of hCAR. Subsequent experiments demonstrated that these three drugs efficiently induced nuclear accumulation of in vivo-transfected enhanced yellow fluorescent protein-hCAR and significantly increased expression of a CYP2B6 reporter gene when hCAR was expressed in CAR-/- mice. In addition, using a recently identified, chemically responsive splice variant of hCAR (hCAR3), the hCAR activation profiles of the 16 compounds were evaluated. By combining results from the hPXR- and hCAR3-based reporter gene assays, these inducers were classified as hPXR, hCAR, or hPXR/hCAR dual activators. Our results demonstrate that CMZ, EFV, and NVP induce CYP2B6 and CYP3A4 preferentially through hCAR and that hCAR3 represents a sensitive tool for in vitro prediction of chemical-mediated human CAR activation.
 ...
PMID:Relative activation of human pregnane X receptor versus constitutive androstane receptor defines distinct classes of CYP2B6 and CYP3A4 inducers. 1704 Oct 8

The xenobiotic-activated nuclear receptors PXR (pregnane X receptor) and CAR (constitutive androstane receptor) and the vitamin D(3)-activated nuclear receptor VDR regulate steroid and xenobiotic metabolism by inducing the phase I cytochrome P450 monooxygenases, phase II conjugating transferases, and the phase III transporters, which mediate the efflux of water-soluble lipid metabolites from cells. Metabolic stress due to the deviant expression of steroid- and xenobiotic-metabolizing enzymes is known to have severe health consequences including accelerated aging, and increased expression of these enzymes is associated with extended longevity [Gachon, F, Olela, FF, Schaad, O, Descombes, P and Schibler, U, 2006. The circadian PAR-domain basic leucine zipper transcription factors DBP, TEF, and HLF modulate basal and inducible xenobiotic detoxification. 4, 25-36.; McElwee, JJ, Schuster, E, Blanc, E, Thomas, JH and Gems, D, 2004. Shared Transcriptional Signature in Caenorhabditis elegans Dauer Larvae and Long-lived daf-2 Mutants Implicates Detoxification System in Longevity Assurance. J. Biol. Chem., 279, 44533-43.]. Information on the similarities and dissimilarities in drug metabolism between the young and old, as may be uncovered by studying aging regulation of the genes relevant to steroid and xenobiotic metabolism, is likely to have clinical significance. In this report, we examined the VDR- and PXR-mediated gene induction of the phase II sulfotransferase Sult2A1 in the livers of 4-month- and 20-month-old mice. Sult2A1 converts bile acids, steroids and a number of drugs to the corresponding sulfated metabolites, which are readily eliminated from the body due to increased water solubility. In RT-PCR assay, aging did not change the induction of Sult2A1 mRNAs by the hormonally active vitamin D(3) and the catatoxic synthetic steroid PCN (pregnenolone-16alpha-carbonitrile). Chromatin immunoprecipitation (ChIP) from liver nuclei showed that aging had no effect on the activity of an IR0 enhancer in the Sult2A1 chromatin to recruit VDR, RXR-alpha (retinoid X receptor) and PXR in mice injected with D(3) or PCN. Thus, mice in late life are as competent as those in early life in responding to the hormonal and xenobiotic signaling for Sult2A1 induction. This is the first report describing the role of aging in the functional response of an enhancer in the liver chromatin to the nuclear receptor-dependent signaling.
 ...
PMID:Xenobiotic- and vitamin D-responsive induction of the steroid/bile acid-sulfotransferase Sult2A1 in young and old mice: the role of a gene enhancer in the liver chromatin. 1712 47

Early in vitro toxicity screening might improve the success rate of new chemical entities in pharmaceutical development. In previous studies, the advantage of cytotoxicity screening with the HepG2 cell line was shown. Cytotoxicity could be identified for 70% of the compounds in these assays as compared with known toxicity in either in vitro assays in primary hepatocytes, in in vivo assays in rats, or in (pre-)clinical development in humans. The low Phase I and II enzyme levels in HepG2 cells might have been responsible for the fact that 30% of the compounds scored negative. Therefore, we performed two follow-up studies in which Cytochrome P450 (CYP) enzymes and Phase II metabolism were examined. In the present study, the transcript levels of CYP1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4 were measured with quantitative PCR. Results showed that transcripts of all CYPs were present in HepG2 cells, however, mRNA levels of most CYPs were dramatically lower than in primary human hepatocytes. These results were confirmed with luminometric assays which were used to measure the enzyme activities of CYP1A1, 1A2, 2C9, and 3A4. Regulation of CYP1A1, 1A2, 2B6, 2C8, 2D6, 2E1, and 3A4 by the aryl hydrocarbon receptor, pregnane X receptor and constitutive androstane receptor was studied in HepG2 cells at the mRNA and/or enzyme level. Regulation of CYP1A1, 1A2, 2B6, and 3A4 mRNA levels was similar to the regulation in primary human hepatocytes. In contrast, CYP2C8 mRNA levels are inducible in primary human hepatocytes, but not in HepG2 cells, after treatment with PXR/CAR activators. Consistent with other studies, CYP2D6 and 2E1 transcript levels were not changed after treatment with AhR, PXR, and CAR activators. Moreover, CYP1A1 and 1A2 enzyme levels could be induced by AhR agonists and CYP3A4 by PXR agonists. As a consequence of the low levels of CYPs in HepG2 cells, cytotoxicity of several compounds might have been missed or underestimated as compared with cytotoxicity in primary human hepatocytes. Inducing HepG2 cells with particular receptor stimulators might lead to higher toxicity for several of the tested compounds. Compared to primary human hepatocytes, HepG2 cells are a relatively easy-to-handle tool to study the up-regulation of CYP1A1, 1A2, 2B6, and 3A4.
 ...
PMID:Cytochrome P450 enzyme levels in HepG2 cells and cryopreserved primary human hepatocytes and their induction in HepG2 cells. 1763 4

Xenobiotic and drug metabolism and transport are managed by a large number of genes coordinately regulated by at least three nuclear receptors or xenosensors: aryl hydrocarbon receptor (AhR), constitutive androstane receptor (CAR, NR1I3), and pregnane X receptor (PXR, NR1I2). Initially characterized as xenosensors, it is now evident that CAR and PXR also trigger pleiotropic effects on liver function. Recent studies have shown the existence of crosstalk between xenosensors and other nuclear receptors or transcription factors controlling endogenous signaling pathways which regulate physiological functions. This review is focused on recent observations showing that activation of CAR and PXR alters lipid metabolism, glucose homeostasis, and inflammation by interfering with HNF4alpha, FoxO1, FoxA2, PGC1alpha, or NFkB p65. Such crosstalks explain clinical observations and provide molecular mechanisms allowing understanding how xenobiotics and drugs may affect physiological functions and provoke endocrine disruptions.
 ...
PMID:Xenoreceptors CAR and PXR activation and consequences on lipid metabolism, glucose homeostasis, and inflammatory response. 1815 29

To investigate how the liver adapts to chronic obstructive cholestasis, liver samples from infants with early- and late-stage cholestasis were analyzed for changes in the levels of hepatocyte transporters and nuclear receptors. At early-stage cholestasis, most canalicular transporters and sinusoidal uptake transporters were downregulated, including bile salt export pump (BSEP, ABCB11), multidrug resistant protein 3 (MDR3, ABCB4), multidrug-resistant associated protein 2 (MRP2, ABCC2), sodium-dependent taurocholate cotransporting polypeptide (NTCP, SLC10A1), organic anion transporter (OATP, SLCO1A2), and nuclear receptor farnesoid X receptor (FXR, NR1H4). At late-stage cholestasis, FXR-BSEP levels returned to normal, MDR3 and MDR1 (ABCB1) were upregulated, and MRP-2 was downregulated. In addition, alternative sinusoidal efflux transporters, organic solute transporter alpha/beta (OSTalpha/beta) and MRP4 were upregulated, and pregnane X receptor (PXR, NR1I2) levels decreased. Cytochrome enzyme P450 7A1 was markedly downregulated at both early and late-stage cholestasis. An analysis of the long-term prognosis of 18 patients revealed lower PXR and constitutive androstane receptor (CAR, NR1I3) levels in the poor prognosis group. In conclusion, at long-term cholestasis, hepatocyte bile efflux was through sinusoidal and canalicular transporters, with FXR-BSEP levels maintained and PXR downregulated. Low PXR and CAR levels were associated with poor prognosis.
 ...
PMID:Expression of hepatocyte transporters and nuclear receptors in children with early and late-stage biliary atresia. 1832 54

Decreased drug metabolism, hyperbilirubinemia and intrahepatic cholestasis are frequently observed during inflammation. Additionally, it has long been appreciated that exposure to drug metabolism-inducing xenobiotics can impair immune function. The nuclear receptor CAR (constitutive androstane receptor or NR1I3) and PXR (pregnane X receptor, NR1I2) control phase I (cytochrome P450 2B and 3A), phase II (GSTA, UGT1A1), and transporter (MDR1, SLC21A6, MRP2) genes involved in drugs metabolism, bile acids and bilirubin clearance in response to xenobiotics. It is well known that inflammation, through the activation of NF-kappaB pathway, leads to a decrease of CAR, PXR and RXRalpha expression and the expression of their target genes. In addition, a new study reveals the mutual repression between PXR and NF-kappaB signaling pathways, providing a molecular mechanism linking xenobiotic metabolism and inflammation.
 ...
PMID:[[Inflammation and drug metabolism: NF-kappB and the CAR and PXR xeno-receptors]. 1833 80

As a promiscuous xenobiotic sensor, the constitutive androstane receptor (CAR; NR1I3) regulates the expression of multiple drug-metabolizing enzymes and transporters in liver. The constitutively activated nature of CAR in the cell-based transfection assays has hindered its use as a predictor of metabolism-based drug-drug interactions. Here, we have identified 1-(2-chlorophenylmethylpropyl)-3-isoquinoline-carboxamide (PK11195), a typical peripheral benzodiazepine receptor (PBR) ligand, as a selective and potent inhibitor of human (h) CAR. In cell-based transfection assays, PK11195 inhibited the constitutive activity of hCAR more than 80% at the concentration of 10 microM, and the PK11195-inhibited activity was efficiently reactivated by the direct CAR activator, 6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde-O-(3,4-dichlorobenzyl) oxime, but not by the indirect hCAR activator, phenobarbital. Mammalian two-hybrid and GST pull-down assays showed that PK11195 repressed the interactions of hCAR with the coactivators steroid receptor coactivator-1 and glucocorticoid receptor-interacting protein 1 to inhibit hCAR activity. The inhibition by PK11195 specifically occurred to the hCAR: PK1195 strongly activated human pregnane X receptor (PXR), whereas it did not alter the activity of the mouse CAR and mouse PXR. In addition, PBR played no role in the PK11195 inhibition of hCAR because the inhibition fully occurred in the HeLa cells in which the PBR was knocked down by small interfering RNA. In the Car(-/-) mouse liver, PK11195 translocated enhanced yellow fluorescent protein-hCAR into the nucleus. These results are consistent with the conclusion that PK11195 is a novel hCAR-specific antagonist that represses the CAR-coactivator interactions to inhibit the receptor activity inside the nucleus. Thus, PK11195 can be used as a chemical tool for studying the molecular basis of CAR function.
 ...
PMID:The peripheral benzodiazepine receptor ligand 1-(2-chlorophenyl-methylpropyl)-3-isoquinoline-carboxamide is a novel antagonist of human constitutive androstane receptor. 1849 98

The liver is responsible for key metabolic functions, including control of normal homoeostasis in response to diet and xenobiotic metabolism/detoxification. We have shown previously that inactivation of the hepatic cytochrome P450 system through conditional deletion of POR (P450 oxidoreductase) induces hepatic steatosis, liver growth and P450 expression. We have exploited a new conditional model of POR deletion to investigate the mechanism underlying these changes. We demonstrate that P450 induction, liver growth and hepatic triacylglycerol (triglyceride) homoeostasis are intimately linked and provide evidence that the observed phenotypes result from hepatic accumulation of unsaturated fatty acids, which mediate these phenotypes by activation of the nuclear receptor CAR (constitutive androstane receptor) and, to a lesser degree, PXR (pregnane X receptor). To our knowledge this is the first direct evidence that P450s play a major role in controlling unsaturated fatty acid homoeostasis via CAR. The regulation of P450s involved in xenobiotic metabolism by this mechanism has potentially significant implications for individual responses to drugs and environmental chemicals.
 ...
PMID:Unsaturated fatty acid regulation of cytochrome P450 expression via a CAR-dependent pathway. 1877 45

Cytochrome P-450 3A (CYP3A) together with its nuclear receptors plays a critical role in drug metabolism. The present study investigated the effects of undernutrition in utero on hepatic mRNA and protein expression of the enzyme CYP3A23/3A1 and nuclear receptors including pregnane X receptor (PXR; NR1I2), constitutive androstane receptor (CAR; NR1I3) and nuclear factor-4alpha (HNF4alpha; HNF4A) in neonatal rats. At gestational day 2, pregnant rats were randomly divided into two groups: nourished (fed ad libitum) and undernourished (50% of nourished group). The pups delivered by nourished rats were designated as the normal-birth-weight group (NBW, n=15) and those delivered by undernourished rats were designated as the low-birth-weight group (LBW, n=15). Hepatic mRNA expression was detected by quantitative real-time PCR and the corresponding protein expression was examined by immunohistochemistry (IHC). Compared with NBW pups, LBW pups tended to have lower mRNA expression levels of CYP3A23/3A1, PXR and CAR but higher levels of HNF4alpha. Only the CAR mRNA expression differences were significant (p<0.05). mRNA expression of CYP3A23/3A1 correlated with that of HNF4alpha in both the LBW(r=0.808, p=0.007) and NBW (r=0.452, p=0.012) groups. CYP3A23/3A1 and CAR protein expression differed between the two groups (CYP3A23/3A1, chi(2)=7.87, p=0.005; CAR, chi(2)=12.069, p=0.001). In conclusion, these findings suggest that undernutrition may influence the mRNA expression of CAR and protein expression of both CYP3A23/3A1 and CAR in neonatal rats. Since CYP3A23/3A1 and CAR are critically involved in drug metabolism, these results may have clinical implications for optimal medication in LBW children.
 ...
PMID:Effects of intrauterine undernutrition on the expression of CYP3A23/3A1, PXR, CAR and HNF4alpha in neonate rats. 1905 92


<< Previous 1 2 3 4 5 6 7 8 9 Next >>