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 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

Microsomal enzyme inducers (MEIs) up-regulate phase I biotransformation enzymes, most notably cytochromes P450. Transcriptional up-regulation by MEIs occurs through at least three nuclear receptor mechanisms: constitutive androstane receptor (CAR; CYP2B inducers), pregnane X receptor (PXR; CYP3A inducers), and peroxisome proliferator-activated receptor alpha (PPARalpha; CYP4A inducers). Other mechanisms include transcription factors aryl hydrocarbon receptor (AhR; CYP1A inducers), and nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2; NADPH-quinone oxidoreductase inducers). UDP-glucuronosyltransferases (UGTs) are phase II biotransformation enzymes that are predominantly expressed in liver and intestine. MEIs increase UGT activity; however, transcriptional regulation of individual UGT isoforms is not completely understood. The purpose of this study was to examine inducibility of individual UGT isoforms and potential mechanisms of transcriptional regulation in rat liver and duodenum. UGT mRNA levels were assessed in liver and duodenum of rats treated with MEIs that activate various transcriptional pathways. All four CAR activators induced UGT2B1 in liver, but not duodenum. UGT1A1, 1A5, 1A6, and 2B12 were induced by at least two CAR activators in liver only. Two PXR ligands induced UGT1A2, but only in duodenum. Two PPARalpha ligands induced UGT1A1 and 1A3 in liver only. AhR ligands induced UGT1A6 and 1A7 in liver, but not duodenum. Nrf2 activators increased UGT2B3 and 2B12 in both liver and duodenum, and UGT1A6, 1A7, and 2B1 in liver only. In summary, only UGT1A2 and 1A8 were not inducible in liver by MEIs. MEIs differentially regulate hepatic expression of individual UGT isoforms, although no one transcriptional pathway dominated. In duodenum, MEIs had minimal effects on UGT expression.
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PMID:Induction of rat UDP-glucuronosyltransferases in liver and duodenum by microsomal enzyme inducers that activate various transcriptional pathways. 1685 52

CAR (constitutive androstane receptor) is a nuclear receptor that regulates the transcription of target genes, including CYP (cytochrome P450) 2B and 3A. The transactivation by CAR is regulated by its subcellular localization; however, the mechanism that governs nuclear translocation has yet to be clarified. It has been reported recently that AMPK (AMP-activated protein kinase) is involved in phenobarbital-mediated CYP2B induction in a particular culture system. We therefore investigated in vivo whether AMPK is involved in the activation of CAR-dependent gene expression. Immunoblot analysis using an antibody which recognizes Thr-172-phosphorylated AMPKalpha1/2 revealed phenobarbital-induced AMPK activation in rat and mouse livers as well. Phenobarbital, however, failed to increase the liver phospho-AMPK level of tumour-bearing rats in which CAR nuclear translocation had been impaired. In in vivo reporter gene assays employing PBREM (phenobarbital-responsive enhancer module) from CYP2B1, an AMPK inhibitor 8-bromo-AMP abolished phenobarbital-induced transactivation. In addition, Cyp2b10 gene expression was attenuated by 8-bromo-AMP. Forced expression of a dominant-negative mutant and the wild-type of AMPKalpha2 in the mouse liver suppressed and further enhanced phenobarbital-induced PBREM-reporter activity respectively. Moreover, the AMPK activator AICAR (5-amino-4-imidazolecarboxamide riboside) induced PBREM transactivation and an accumulation of CAR in the nuclear fraction of the mouse liver. However, AICAR and metformin, another AMPK activator, failed to induce hepatic CYP2B in mice and rats. These observations suggest that AMPK is at least partly involved in phenobarbital-originated signalling, but the kinase activation by itself is not sufficient for CYP2B induction in vivo.
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PMID:A physiological role of AMP-activated protein kinase in phenobarbital-mediated constitutive androstane receptor activation and CYP2B induction. 1703 73

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.
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PMID:Relative activation of human pregnane X receptor versus constitutive androstane receptor defines distinct classes of CYP2B6 and CYP3A4 inducers. 1704 Oct 8

Cytochrome P450 of the 2B subfamily is easily induced by many xenobiotics. In spite of intensive investigations, the molecular mechanisms of regulation of the CYP2B genes are not clear. The nuclear receptor CAR is shown to play a crucial role in the activation of CYP2B genes by xenobiotics, but many problems of CAR activation in different animal species and humans remain unsolved. This review focuses on signaling pathways involved in the control of CYP2B gene expression in mammals.
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PMID:Induction of cytochrome P4502B: role of regulatory elements and nuclear receptors. 1763 Sep 5

The transcript levels of CYP2B22, 3A22, 3A29, 3A46, CAR, PXR and HNF4alpha were investigated in liver, kidney and airways from control and rifampicin-treated male pigs. The presence and induction of CYP genes transcription were studied by RT-PCR, real-time PCR, Western blotting and enzymatic activity whereas the expression of receptors was studied by RT-PCR or real-time PCR. Pretreatment with rifampicin resulted in a transcriptional activation, although to different extents, of all the CYP3A genes in liver but not in kidney, lung, bronchi or trachea. In the hepatic microsomes, the induction of CYP3A genes was accompanied by an increase of CYP3As marker activities and of two protein bands immunoreactive with anti-human CYP3A4. The CYP2B22 transcript was found to be markedly induced only in liver and kidney. In parallel, a protein band immunoreactive with anti-rat CYP2B1 was elevated while enhanced CYP2B marker activities were observed in hepatic and renal microsomes. As expected, based on human data, the basal expression of CAR, PXR and HNF4alpha was found to be high in liver and low in airways and not susceptible to induction by rifampicin. A significant expression of these transcriptional factors was also demonstrated in kidney. Thus, it is likely that rifampicin induced CYP2B22 both in liver and kidney of pig, not via activation of CAR, but via PXR, through a cross-talk mechanism, as previously observed in human liver. Taken together, our results demonstrated a differential expression and regulation of three individual CYP3As, CYP2B22, CAR, PXR and HNF4alpha genes in liver, kidney and airways of pig.
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PMID:Expression and induction by rifampicin of CAR- and PXR-regulated CYP2B and CYP3A in liver, kidney and airways of pig. 1878 98

Two-year treatment with high doses of Metofluthrin produced hepatocellular tumors in both sexes of Wistar rats. To understand the mode of action (MOA) by which the tumors are produced, a series of studies examined the effects of Metofluthrin on hepatic microsomal cytochrome P450 (CYP) content, hepatocellular proliferation, hepatic gap junctional intercellular communication (GJIC), oxidative stress and apoptosis was conducted after one or two weeks of treatment. The global gene expression profile indicated that most genes with upregulated expression with Metofluthrin were metabolic enzymes that were also upregulated with phenobarbital. Metofluthrin induced CYP2B and increased liver weights associated with centrilobular hepatocyte hypertrophy (increased smooth endoplasmic reticulum [SER]), and induction of increased hepatocellular DNA replication. CYP2B1 mRNA induction by Metofluthrin was not observed in CAR knockdown rat hepatocytes using the RNA interference technique, demonstrating that Metofluthrin induces CYP2B1 through CAR activation. Metofluthrin also suppressed hepatic GJIC and induced oxidative stress and increased antioxidant enzymes, but showed no alteration in apoptosis. The above parameters related to the key events in Metofluthrin-induced liver tumors were observed at or below tumorigenic dose levels. All of these effects were reversible upon cessation of treatment. Metofluthrin did not cause cytotoxicity or peroxisome proliferation. Thus, it is highly likely that the MOA for Metofluthrin-induced liver tumors in rats is through CYP induction and increased hepatocyte proliferation, similar to that seen for phenobarbital. Based on analysis with the International Life Sciences Institute/Risk Science Institute MOA framework, it is reasonable to conclude that Metofluthrin will not have any hepatocarcinogenic activity in humans, at least at expected levels of exposure.
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PMID:Mode of action analysis for the synthetic pyrethroid metofluthrin-induced rat liver tumors: evidence for hepatic CYP2B induction and hepatocyte proliferation. 1917 66

The presence and inducibility of specific CYPs (1A1, 1A2, 1B1, 2B22, 3A22, 3A29 and 3A46) and the related transcriptional factors (AhR, CAR, PXR, and HNF4alpha) were investigated, at activity and/or transcriptional level, in liver, respiratory and olfactory mucosa of control and beta-naphthoflavone (betaNF)-treated pigs an agonist of AhR, or rifampicin (RIF), an agonist of PXR. Experiments with real-time PCR showed that CYP1A1 mRNA was enhanced by betaNF, although at different extent, in liver, respiratory and olfactory tissues, whereas mRNAs of CYP1A2 and 1B1 were increased only in liver. Accordingly, in microsomes of both nasal tissues, the transcriptional activation of CYP1A1 was accompanied by an induction of ethoxyresorufin deethylase activity (a marker of this isoform) but not of methoxyresorufin demethylase activity (a marker of CYP1A2). The rifampicin treatment resulted in a transcriptional activation of CYP2B22 and CYP3As genes in liver but not in respiratory and olfactory mucosa. In parallel, the marker activity of CYP2B (ethoxy 4-(trifluoromethyl)coumarin deethylase) and CYP3As (6beta-testosterone hydroxylase and benzyloxyquinoline debenzylase) were induced in liver microsomes but not in the nasal ones. Considering the transcriptional factors, the basal expression of AhR mRNA was found to be as high in liver as in both nasal tissues but not susceptible to induction by betaNF. Also PXR mRNA was found, aside liver, well expressed in the nasal tissues, whereas CAR and HNF4alpha mRNAs were barely detected. In any case, these transcripts appeared to be enhanced by RIF treatment. Our results demonstrated that in the respiratory and olfactory mucosa of pig, although the presence of AhR, only CYP1A1, but not 1A2 and 1B1 resulted to be inducible by betaNF. Similarly, it was observed that in these nasal tissues, although the presence of PXR, neither CYP2B22 nor any CYP3A resulted to be inducible by RIF. Thus, the regulation mechanism of CYP1A2, 1B1, 2B22, 3A22, 3A29, and 3A46, in the nasal mucosa involves tissue-enriched transcriptional factors others than AhR, CAR, PXR, and HNF4alpha, which are fundamental in liver.
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PMID:Expression and inducibility of CYP1A1, 1A2, 1B1 by beta-naphthoflavone and CYP2B22, 3A22, 3A29, 3A46 by rifampicin in the respiratory and olfactory mucosa of pig. 1946 68

The in vivo effect of rifampicin, a potent ligand of PXR, on gene expression of CYP2B22, 3A22, 3A29, 3A46, CAR, PXR and MDR1, MRP1, MRP2, LRP transporters in liver and cortex, cerebellum, midbrain, hippocampus, meninges and brain capillaries of pig was investigated. Animals were treated i.p. with four daily doses of rifampicin (40 mg/kg). The basal mRNA expressions of the individual CYP3As, CYP2B22, CAR, and PXR in various brain regions, except meninges, were about or below 10% of the corresponding hepatic mRNA values, whereas the mRNAs of brain transporters were closer or comparable to those in liver. After pig treatment with rifampicin, the mRNA expression of CYPs and transporters from brain regions did not appear to change, except CYP3A22 and 3A29 in cortex and hippocampus, CYP2B22 in meninges. An enzymatic analysis for CYP3As and CYP2B, in microsomes and mitochondria from liver and brain tissues using the marker activities 7-benzyloxyquinoline O-debenzylase and the anthraldehyde oxidase, showed the lack of rifampicin induction in all the brain regions, unlike liver. Taken together, our results demonstrate that CYP2B22, CYP3As, and MDR1, MRP1, MRP2, and LRP transporters are all expressed, although at different extent, in the brain regions but, despite the presence of PXR and CAR, are resistant to induction indicating that the regulation of these proteins is more complex in brain than in liver. These data obtained in vivo in the brain regions and liver of pig may be of interest to human metabolism in CNS.
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PMID:Expression and distribution of CYP3A genes, CYP2B22, and MDR1, MRP1, MRP2, LRP efflux transporters in brain of control and rifampicin-treated pigs. 1984 75

The constitutive androstane receptor (CAR; NR1I3) is a key transcriptional factor that regulates genes encoding drug-metabolizing enzymes and drug transporters. However, studies on regulation of CAR target genes via up- or down-regulation of CAR are limited. In this study, we examined the effects of PPARalpha agonists (ciprofibrate, bezafibrate, fenofibrate and WY14643) on the expression of CAR and its target gene CYP2B1/2 in rat primary hepatocytes. Results from real-time PCR analysis showed that CAR and CYP2B1/2 mRNAs exhibit increases in response to all PPARalpha agonists studied (5 to 10-folds of control). Pretreatment of cells with cycloheximide, an inhibitor of protein synthesis, completely suppressed increase in CYP2B1/2 mRNA in response to ciprofibrate, suggesting that protein synthesis is required in this process. In addition, the induction of CAR by ciprofibrate on the protein level was observed with nuclear extracts as well as total cell lysates. These results indicate that CYP2B1/2 mRNAs are induced by PPARalpha agonists and that this effect is accompanied by increase in the expression of CAR gene at both mRNA and nuclear protein levels. Activated PPARalpha may increase functional CAR protein, which can induce the expression of CAR target genes such as CYP2B.
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PMID:Peroxisome proliferator-activated receptor alpha (PPARalpha) agonists induce constitutive androstane receptor (CAR) and cytochrome P450 2B in rat primary hepatocytes. 2020 94


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