Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.14.13.97 (CYP3A4)
 6,365 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
 ...
PMID:Dexamethasone enhances constitutive androstane receptor expression in human hepatocytes: consequences on cytochrome P450 gene regulation. 1109 84

The fully active dihydroxylated metabolite of vitamin D(3) induces the expression of CYP3A4 and, to a lesser extent, CYP2B6 and CYP2C9 genes in normal differentiated primary human hepatocytes. Electrophoretic mobility shift assays and cotransfection in HepG2 cells using wild-type and mutated oligonucleotides revealed that the vitamin D receptor (VDR) binds and transactivates those xenobiotic-responsive elements (ER6, DR3, and DR4) previously identified in CYP3A4, CYP2B6, and CYP2C9 promoters and shown to be targeted by the pregnane X receptor (PXR) and/or the constitutive androstane receptor (CAR). Full VDR response of various CYP3A4 heterologous/homologous promoter-reporter constructs requires both the proximal ER6 and the distal DR3 motifs, as observed previously with rifampicin-activated PXR. Cotransfection of a CYP3A4 homologous promoter-reporter construct (including distal and proximal PXR-binding motifs) and of PXR or CAR expression vectors in HepG2 cells revealed the ability of these receptors to compete with VDR for transcriptional regulation of CYP3A4. In conclusion, this work suggests that VDR, PXR, and CAR control the basal and inducible expression of several CYP genes through competitive interaction with the same battery of responsive elements.
 ...
PMID:Expression of CYP3A4, CYP2B6, and CYP2C9 is regulated by the vitamin D receptor pathway in primary human hepatocytes. 1199 50

Cytochromes P450 (CYP) constitute the major enzymatic system for metabolism of xenobiotics. Here we demonstrate that transcriptional activation of CYPs by the drug-sensing nuclear receptors pregnane X receptor, constitutive androstane receptor, and the chicken xenobiotic receptor (CXR) can be modulated by endogenous cholesterol and bile acids. Bile acids induce the chicken drug-activated CYP2H1 via CXR, whereas the hydroxylated metabolites of bile acids and oxysterols inhibit drug induction. The cholesterol-sensing liver X receptor competes with CXR, pregnane X receptor, or constitutive androstane receptor for regulation of drug-responsive enhancers from chicken CYP2H1, human CYP3A4, or human CYP2B6, respectively. Thus, not only cholesterol 7 alpha-hydroxylase (CYP7A1), but also drug-inducible CYPs, are diametrically affected by these receptors. Our findings reveal new insights into the increasingly complex network of nuclear receptors regulating lipid homeostasis and drug metabolism.
 ...
PMID:Cholesterol and bile acids regulate xenosensor signaling in drug-mediated induction of cytochromes P450. 1204 1

Although CYP2C8, CYP2C9, and CYP2C19 play an important role in drug biotransformation, factors influencing the expression and activity of these CYP2C P450s in human liver remain largely undefined. We used primary cultures of human hepatocytes from 15 subjects to assess the inducibility of CYP2C enzyme expression by prototypical inducer agents, including rifampicin, dexamethasone, and phenobarbital. After culture for 72 h in serum-free medium on collagen, Western blotting revealed that CYP2C9 was the only CYP2C enzyme expressed at appreciable levels in untreated hepatocytes. Subsequent treatment with 25 microMrifampicin for 48 h elicited marked increases in CYP2C8 (700 +/- 761%), CYP2C19 (854%), and CYP2C9 (209 +/- 176%) protein content versus a 550 +/- 170% enhancement of CYP3A4 enzyme levels. Parallel increases in CYP2C mRNAs, measured by Northern blotting and/or RNase protection, were found in rifampicin-treated hepatocytes, with CYP2C8, CYP2C9, and CYP2C19 transcripts exhibiting increases of 688 +/- 635, 207 +/- 49, and 230 +/- 60%, respectively, versus an 8.8-fold enhancement of CYP3A4 mRNA levels. Dexamethasone (10 microM) treatment enhanced CYP2C8 mRNA (360 +/- 100%) and protein (274%) content, although this steroid had less effect on CYP2C9 and CYP2C19 transcripts (23 +/- 21% and 21 +/- 36%, respectively) and enzyme levels (55 and 143%, respectively). Phenobarbital (100 microM) was a powerful inducer of CYP2C9 (850%) and CYP2C19 (735%) mRNA content, and also increased CYP2C8 (610%) and CYP3A4 (205%) transcripts. Our results show that CYP2C enzyme expression in human hepatocytes is highly inducible by rifampicin, dexamethasone, and phenobarbital. Because these xenobiotics are ligands and/or activators of the pregnane X receptor and/or constitutive androstane receptor, such orphan nuclear receptors and their response elements may partake in regulating CYP2C gene expression in humans.
 ...
PMID:Expression and induction of CYP2C P450 enzymes in primary cultures of human hepatocytes. 1213 Jul 4

CYP3A4 is the most abundant cytochrome P450 (P450) in human liver, comprising approximately 30% of the total liver P450 content. This enzyme has an important role in steroid catabolism and metabolism of foreign compounds, with the majority of pharmaceutical compounds being substrates for CYP3A4. The molecular mechanisms that underlie transcriptional activation of CYP3A4 are complex with many steroid hormone nuclear receptors, including glucocorticoid receptor, pregnane X receptor (PXR), vitamin D receptor, and constitutive androstane receptor, playing roles. Nowhere is this more evident than in the induction of CYP3A4 gene expression by glucocorticoids. CYP3A genes lack a consensus glucocorticoid receptor response element and yet are highly induced by classical glucocorticoids such as hydrocortisone and dexamethasone. Recent evidence has demonstrated that glucocorticoids are ligands for the orphan nuclear receptor PXR, and induction of CYP3A genes by glucocorticoids may occur primarily through PXR interactions. In this paper, we present a mutant that disrupts a hepatocyte-nuclear-factor-3/CCAAT-enhancer binding protein alpha binding site in the CYP3A4 proximal promoter. This mutation disrupts induction of a reporter gene construct by the glucocorticoids dexamethasone and hydrocortisone; yet induction by the potent PXR ligand rifampicin is unaffected. Such data provides strong evidence that glucocorticoids induce CYP3A4 gene expression both through the established PXR-dependent pathway but also through a PXR-independent pathway.
 ...
PMID:Glucocorticoid-mediated induction of CYP3A4 is decreased by disruption of a protein: DNA interaction distinct from the pregnane X receptor response element. 1216 69

Numerous chemicals increase the metabolic capability of organisms by their ability to activate genes encoding various xenochemical-metabolizing enzymes, such as cytochromes P450 (CYPs), transferases and transporters. For example, natural and synthetic glucocorticoids (agonists and antagonists) as well as other clinically important drugs induce the hepatic CYP2B, CYP2C and CYP3A subfamilies in man, and these inductions might lead to clinically important drug-drug interactions. Only recently, the key cellular receptors that mediate such inductions have been identified. They include nuclear receptors, such as the constitutive androstane receptor (CAR, NR1I3), the retinoid X receptor (RXR, NR2B1), the pregnane X receptor (PXR, NR1I2), and the vitamin D receptor (VDR, NR1I1) and steroid receptors such as the glucocorticoid receptor (GR, NR3C1). There is a wide promiscuity of these receptors in the induction of CYPs in response to xenobiotics. Indeed, this adaptive system appears now as a tangle of networks, where receptors share partners, ligands, DNA response elements and target genes. Moreover, they influence mutually their relative expression. This review is focused on these different pathways controlling human CYP2B6, CYP2C9 and CYP3A4 gene expression, and the cross-talk between these pathways.
 ...
PMID:The expression of CYP2B6, CYP2C9 and CYP3A4 genes: a tangle of networks of nuclear and steroid receptors. 1257 84

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.
 ...
PMID:[The role of nuclear receptors in cytochrome P-450 induction by xenochemicals]. 1266 59

CYP3A4, the predominant but variably expressed cytochrome P450 of adult human liver, is subject to multifaceted constitutive regulation as well as transcriptional induction by a variety of structurally unrelated xenobiotics. Using transient transfections in HepG2 cells, we previously demonstrated the existence of a potent xenobiotic-responsive enhancer module located between - 7.2 and - 7.8 kilobases upstream of the CYP3A4 transcription start site. Induction is mediated by interaction of transcription factor binding sites in the XREM with the nuclear receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR). To determine the in vivo relevance of these findings and to establish a mouse model of human CYP3A4 regulation, we have generated transgenic mice carrying constructs comprising the upstream regulatory region of the human CYP3A4 gene linked to the lacZ reporter gene. Constitutive expression was observed in a developmental, tissue- and cell-specific fashion that mirrors the human situation. In addition, robust hepatic and intestinal induction with a range of reagents known to activate PXR and/or CAR (e.g., dexamethasone, pregnenolone 16alpha-carbonitrile, and phenobarbital) was observed. However, no expression or induction was apparent with a construct lacking upstream sequences beyond - 3.2 kilobases. Histochemical staining for beta-galactosidase activity revealed that dose-dependent increases in transgene levels were associated with a zonal expansion of lacZ expressing hepatocytes, suggesting that xenobiotic induction of CYP3A genes operates primarily through the recruitment of more cells committed to expression. In summary, CYP3A4/lacZ transgenic mice provide an in vivo model for the study of the molecular mechanisms involved in the regulation of a significant human drug metabolizing enzyme.
 ...
PMID:Transgenic mouse models of human CYP3A4 gene regulation. 1281 59

The xenobiotic-mediated induction of three major human liver cytochrome P450 genes, CYP2B6, CYP2C9, and CYP3A4, is known to be regulated by the constitutive androstane receptor (CAR) and the pregnane X receptor (PXR). CAR and PXR are regulated, at least in part, by the glucocorticoid receptor (GR) and the hypothesis of a signal transduction cascade GR-[CAR/PXR]-P450 has been proposed. This study was aimed at testing this hypothesis in primary human hepatocytes by using the tubulin network disrupting agent colchicine. Colchicine (COL) decreased both basal and rifampicin- and phenobarbital-inducible expression of CYP2B6, CYP2C8/9, and CYP3A4. A parallel down-regulation of mRNA expression of CAR, PXR, and tyrosine aminotransferase, a prototypic gene directly regulated by GR, was observed. COL affected neither the level of GR mRNA nor ligand binding to GR. To evaluate the effect of colchicine on GR-mediated gene transactivation, HeLa cells stably or transiently transfected with a GR-responsive element-dependent luciferase reporter gene were used. COL decreased the dexamethasone-induced luciferase expression in stably transfected cell line by 50%, whereas GR transactivation in transiently transfected cells was not affected by COL. In contrast, ligand-dependent GR translocation in the human embryonic kidney 293 cell line transiently transfected with GFP-GR was inhibited by COL. We conclude that alteration of the signal transduction mediated through the GR-[CAR/PXR]-P450 cascade by colchicine is responsible for the down-regulation of CYP2C9 and CYP3A4, implicating cytoskeleton as necessary for correct functioning of this cascade under physiological conditions.
 ...
PMID:Colchicine down-regulates cytochrome P450 2B6, 2C8, 2C9, and 3A4 in human hepatocytes by affecting their glucocorticoid receptor-mediated regulation. 1281 72

All-trans-retinoic acid (ATRA) is used in the treatment of promyelocytic acute leukemia. The biotransformation of this drug is catalyzed by various cytochrome P450 (CYP) enzymes, but relatively little is known about the effect of ATRA on CYP enzyme expression in leukemic cells. In the present study, we conducted transcript profiling of CYP and related genes in cultured HL-60 human promyelocytic leukemic cells and determined the effect of ATRA on the expression of these genes. Reverse transcription-polymerase chain reaction (RT-PCR) analysis with a block-cycler indicated the presence of CYP1B1 but not CYP1A1, CYP2B6, CYP2C8, CYP2C9, CYP3A4, CYP3A5, or CYP26A1 transcript in cultured HL-60 cells. ATRA treatment (0.1-40 microM for 3 days) increased CYP1B1 mRNA levels by up to 3 fold, as determined by a quantitative real-time PCR method. The same ATRA treatment also resulted in the detection of CYP26A1 but not CYP1A1, CYP2B6, CYP2C8, CY2C9, CYP3A4, or CYP3A5 mRNA. Additional experiments showed that phenobarbital increased CYP2B6 mRNA expression and that pregnane X receptor (PXR) but not constitutive androstane receptor (CAR) was detected in HL-60 cells. Overall, our novel findings indicate the upregulation of CYP1B1 by ATRA in HL-60 human promyelocytic leukemic cells shown for the first time to express PXR but not CAR mRNA.
 ...
PMID:Transcript profiling of cytochrome P450 genes in HL-60 human leukemic cells: upregulation of CYP1B1 by all-trans-retinoic acid. 1287 Jun 55


1 2 3 4 5 6 7 8 9 10 Next >>