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)

During the inflammatory response, intrahepatic cholestasis and decreased drug metabolism are frequently observed. At the hepatic level, the orphan nuclear constitutive androstane receptor (CAR) (NR1I3) controls phase I (cytochrome P450 [CYP] 2B and CYP3A), phase II (UGT1A1), and transporter (SLC21A6, MRP2) genes involved in drug metabolism and bilirubin clearance in response to xenobiotics such as phenobarbital or endobiotics such as bilirubin. We investigated the negative regulation of CAR, a glucocorticoid-responsive gene, via proinflammatory cytokine interleukin 1beta (IL-1beta) and lipopolysaccharides (LPSs) in human hepatocytes. We show that IL-1beta decreases CAR expression and decreases phenobarbital- or bilirubin-mediated induction of CYP2B6, CYP2C9, CYP3A4, UGT1A1, GSTA1, GSTA2, and SLC21A6 messenger RNA. This occurs via nuclear factor kappaB (NF-kappaB) p65 activation, which interferes with the enhancer function of the distal glucocorticoid response element that we have identified recently in the CAR promoter. We demonstrate that: (1) LPSs, IL-1beta, or overexpression of p65RelA inhibit glucocorticoid receptor (GR)-mediated CAR transactivation; (2) these suppressive effects can be blocked both by pyrrolidine dithiocarbamate, an inhibitor of NF-kappaB activation, or by overexpression of SRIkBalpha, a NF-kappaB repressor; and (3) the GR agonist dexamethasone induces histone H4 acetylation at the proximal CAR promoter region, whereas LPSs and IL-1beta inhibit this acetylation as assessed via chromatin immunoprecipitation assay. In conclusion, GR/NF-kappaB interaction affects CAR gene transcription through chromatin remodeling and provide a mechanistic explanation for the long-standing observation that inflammation and sepsis inhibit drug metabolism while inducing intrahepatic cholestasis or hyperbilirubinemia.
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PMID:Interleukin 1beta inhibits CAR-induced expression of hepatic genes involved in drug and bilirubin clearance. 1538 19

Archived tumor tissue is a useful resource for retrospective studies addressing relationships between genetic polymorphisms and treatment outcomes. However, genotypes determined in tumor and somatic tissues may differ due to cytogenetic and molecular changes associated with malignant transformation and progression. Discordance between germ line and tumor genotypes may be particularly relevant in leukemia because cytogenetic abnormalities are frequent. We compared genotypes determined in DNA extracted from paired pretreatment bone marrow and buccal samples from 80 adult patients with acute myeloid leukemia (AML). Paired AML and buccal DNA samples were genotyped for polymorphisms (21 single nucleotide polymorphisms and 2 gene deletions) on genes encoding proteins involved in drug metabolism (CYP3A4, CYP2C8, CDA, and GSTP1), oxidative stress mechanisms (CAT, MnSOD, GSTT1, GSTM1, GSTA1, and GPX1), drug transport (MDR1, MRP1, and BCRP), and DNA repair (MGMT, XPD, and XRCC1). Genotypes were determined by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, except GSTM1 and GSTT1, for which deletion genotypes were determined using multiplex PCR. Concordance of genotypes was tested by kappa statistics. kappa statistics for paired AML and buccal DNA samples ranged between 0.94 and 1.00, indicating excellent agreement. The GSTT1 and GSTM1 genotypes were in perfect concordance for the paired samples. Agreement was also excellent for genes at AML chromosome deletion and translocation breakpoints, including MDR1 at 7q21.1 and MRP1 at 16p13.1. Based on these data, genotypes derived from archived AML bone marrow samples were not likely to differ from those from genomic DNA, and archived bone marrow samples may be useful for the conduct of retrospective pharmacogenetic studies.
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PMID:Concordance of pharmacogenetic polymorphisms in tumor and germ line DNA in adult patients with acute myeloid leukemia. 1750 36

Cattle represent an important source of animal-derived food-products; nonetheless, our knowledge about the expression of drug-metabolizing enzymes (DMEs) in present and other food-producing animals still remains superficial, despite the obvious toxicological consequences. Breed represents an internal factor that modulates DME expression and catalytic activity. In the present work, the effect of breed upon relevant phase I and phase II DMEs was investigated at the pretranscriptional and post-translational levels in male Charolais (CH), Piedmontese (PM) and Blonde d'Aquitaine (BA) cattle. Because specific substrates for cattle have not yet been identified, the breed effect upon specific cytochrome P450 (P450), UDP-glucuronosyltransferase (UGT), or glutathione S-transferase (GST) DMEs, in terms of catalytic activity, was determined by using human marker substrates. Among P450s, benzphetamine N-demethylase, 16beta-, 6beta-, and 2beta-testosterone hydroxylase, aniline and p-nitrophenol hydroxylase, and alpha-naphthol and p-nitrophenol UGT activities were significantly higher in CH; in contrast, lower levels of CYP1A1-, CYP1A2-, CYP2B6-, CYP2C9-, CYP2C18-, CYP3A4-, and UGT1A1-like mRNAs were noticed, with CH < PM < or = BA as a trend. CYP2B and CYP3A mRNA results were confirmed with immunoblotting, too. As regards conjugative DMEs, UGT1A6-like mRNA levels were consistent with respective catalytic activities. Both 1-chloro-2,4-dinitrobenzene and 3,4-dichloronitrobenzene GST activities were higher in BA, and these results agreed with GSTA1-, GSTM1-, and GSTP1-like mRNA amounts. Correlation analysis between catalytic activities and mRNAs showed either significant or uneven results, depending on the substrate. These findings confirm previous data obtained in laboratory species; however, further studies are required to ascribe this behavior to pretranscriptional or post-translational phenomena.
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PMID:Effect of breed upon cytochromes P450 and phase II enzyme expression in cattle liver. 1826 77

The genetic background may modify the individual's risk of developing cancer. We performed a case-control study to test the impact of genomic polymorphisms of 9 genes involved in xenobiotics detoxification and DNA repair in myelodysplastic syndromes (MDS). Frequencies of polymorphic variants of RAD51, XRCC3, NQO1, GSTA1, GSTM1, GSTT1, CYP3A4 and XPD enzymes were similar in patients and controls. On the other hand, the GSTP1-105Val allele was associated to an increased risk of MDS (O.R. 1.66; p=0.04) and to higher probability of overall survival in the low/intermediate-1 IPSS risk group (p=0.008). The GSTP1-Ile105Val polymorphism is likely to influence MDS risk and prognosis.
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PMID:Polymorphisms of detoxification and DNA repair enzymes in myelodyplastic syndromes. 1902 52

Cyclophosphamide (CPA)-based combination treatment has known to be effective for breast cancer, but often causes adverse drug reactions (ADRs). Hence, the identification of patients at risk for toxicity by CPA is clinically significant. In this study, a stepwise case-control association study was conducted using 403 patients with breast cancer who received the CPA combination therapy. A total of 143 genetic polymorphisms in 13 candidate genes (CYP2B6, CYP2C9, CYP2C19, CYP3A4, CYP3A5, ALDH1A1, ALDH3A1, GSTA1, GSTM1, GSTP1, GSTT1, ABCC2 and ABCC4), possibly involved in the activation, metabolism and transport of CPA, were genotyped using 184 cases who developed either > or =grade 3 leukopenia/neutropenia or > or =grade 2 gastrointestinal toxicity and 219 controls who did not show any ADRs throughout the treatment. The association study revealed that one SNP, rs9561778 in ABCC4, showed a significant association with CPA-induced ADRs (Cochran-Armitage trend's P-value=0.00031; odds ratio (OR)=2.06). Subgroup analysis also indicated that the SNP rs9561778 was significantly associated with two major ADR subgroups; gastrointestinal toxicity and leukopenia/neutropenia (Cochran-Armitage trend's P-value=0.00019 and 0.014; OR=2.31 and 1.83). Furthermore, the SNP rs9561778 showed an association with breast cancer patients who were treated with CA(F) drug regimen-induced ADR (Cochran-Armitage trend's P-value=0.00028; OR=3.13). The SNPs in ABCC4 might be applicable in predicting the risk of ADRs in patients receiving CPA combination chemotherapy.
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PMID:Association study of genetic polymorphism in ABCC4 with cyclophosphamide-induced adverse drug reactions in breast cancer patients. 1969 93

We examined the effects of model activators of mitogen-activated protein kinases (MAPKs) on basal and rifampicin-, phenobarbital- and dioxin-inducible expression of phase I and phase II biotransformation enzymes in primary human hepatocytes. Cells were treated for 24 h with sorbitol (SOR), anisomycin (ANI) and epidermal growth factor (EGF) in the presence or absence of inducers. The levels of CYP1A1, CYP1A2, CYP2B6, CYP3A4, UGT1A1, UGT2B17, SULT1A1, SULT2A1, SULT1B2, GSTA1, GSTA2 mRNAs were determined. SOR and EGF inhibited the expression of the tested genes, while ANI had no effect. We conclude that MAPKs play important role in the transcriptional regulation of drug-metabolizing enzymes.
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PMID:Activation of MAPKs influences the expression of drug-metabolizing enzymes in primary human hepatocytes. 2003 98

Therapy-related myeloid neoplasms (t-MNs) are an increasingly recognized complication in patients previously treated with radiotherapy and/or chemotherapy for cancer or autoimmune disease. Single nucleotide variants (SNVs) in genes involved in the cellular pathways of detoxification, DNA repair and apoptosis may modify the individual risk of developing a t-MN. We studied the frequency of the SNVs of six genes involved in xenobiotic detoxification (CYP3A4, NQO1, GSTA1, GSTM1, GSTP1 and GSTT1), two DNA repair genes (RAD51 and XRCC3) and one key regulator of apoptosis (BCL2L10) in a case-control study including 111 cases of t-MN and 259 controls. This is the first report on the prevalence of BCL2L10 Leu21Arg polymorphism in myeloid malignancies. In this line, we also tested 146 cases of de novo myelodysplastic syndrome (MDS) and 109 cases of de novo acute myeloid leukemia (AML). Our results showed a significantly lower frequency of the BCL2L10-21Arg allele in patients with t-MN and de novo MDS compared to controls (Leu/Arg + Arg/Arg: 50.6% vs. 65.9%, p = 0.017 and 45.8% vs. 65.9%, p = 0.0003, respectively). Carriers of the BCL2L10-21Arg variant have a reduced risk of developing t-MN and de novo MDS.
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PMID:The BCL2L10 Leu21Arg variant and risk of therapy-related myeloid neoplasms and de novo myelodysplastic syndromes. 2404 76

Neferine is a bisbenzylisoquinoline alkaloid isolated from the seed embryos of Nelumbonucifera Gaertn (Lotus) with various potent pharmacological effects. Recently, neferine has attracted attention for its anti-tumor activities. Our study explored its metabolism and cytotoxicity mechanism. Approaches using chemical inhibitors and recombinant human enzymes to characterize the involved enzymes and kinetic studies indicated that the demethylation of neferine by cytochrome P450 (CYP) 2D6 and CYP3A4 fitted a biphasic kinetic profile. Glutathione (GSH) was used as a trapping agent to identify reactive metabolites of neferine, and four novel GSH conjugates were detected with [M+H](+) ions at m/z 902.4, 916.2, 916.1, and 930.4. Based on its structure containing para-methylene phenol and results from a product ion scan, GSH tends to conjugate with C9' after undergoing oxidative metabolism to form the binding site predominated by CYP3A4. Furthermore, the addition of recombinant human GSTA1, GSTT1, and GSTP1 had little effect on the production of the GSH conjugates. In a 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide assay, combined with the GSH modulators l-buthionine sulfoximine or N-acetyl-l-cysteine, neferine treatment of MDCK-hCYP3A4 and HepG2 cells revealed that CYP3A4 expression and cellular GSH content could cause an EC50 shift. Metabolic activation mediated by CYP3A4 and GSH depletion significantly enhanced neferine-induced cytotoxicity.
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PMID:Demethylation of neferine in human liver microsomes and formation of quinone methide metabolites mediated by CYP3A4 accentuates its cytotoxicity. 2545 76

Recently, valuable characteristics of menstrual blood stem cells (MenSCs) have impelled scientists to take its advantages for cell therapy of different diseases including liver disorders. In this study, we examined messenger RNA (mRNA) expression levels of phases I and II drug metabolizing enzymes including glutathione S-transferase (GST) and cytochrome P-450 (CYP) in differentiated hepatocyte-like cells from MenSCs. The isolated MenSCs were characterized and differentiated into hepatocyte-like cells using hepatocyte growth factor (HGF) and oncostatin M (OSM) in combination with other components in serum-free culture media. After primary characterization of hepatocyte markers, mRNA expression of GSTA1, GSTA2, GSTP1, CYP3A4, and CYP7A1 was assessed in differentiated cells in reference to undifferentiated cells using real-time PCR. Based on immunofluorescent staining and real-time PCR data, the differentiated MenSCs could express functional hepatocyte markers at mRNA and/or protein levels suggesting development of hepatocyte-like cells from MenSCs. Moreover, the expression levels of GSTA1, GSTA2, and CYP3A4 mRNA were upregulated in differentiated cells compared to undifferentiated cells. The expression of CYP7A1 gene was also remarkable on the last day of differentiation process. However, the expression level of GSTP1 did not exhibit statistically significant change during differentiation (P = 0.6). Based on accumulative data, MenSCs could be viewed as an accessible population of stem cells with differentiation ability into drug-metabolizing hepatocyte-like cells.
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PMID:Gene expression pattern of some classes of cytochrome P-450 and glutathione S-transferase enzymes in differentiated hepatocytes-like cells from menstrual blood stem cells. 2561 36

Primary duck hepatocytes (PDH) displays differential susceptibility to duck hepatitis B virus when maintained in the media supplemented with fetal bovine serum or dimethyl sulfoxide (DMSO) which has been widely used for the maintenance of hepatocytes, and prolonging susceptibility to hepadnavirus. However the mechanism underlying maintenance of susceptibility to hepadnavirus by DMSO treatment remains unclear. In this study, a global transcriptome analysis of PDHs under different culture conditions was conducted for investigating the effects of DMSO on maintenance of susceptibility of PDH to DHBV in vitro. The 384 differential expressed genes (DEGs) were identified by comparisons between each library pair (PDHs cultured with or without DMSO or fresh isolated PDH). We analyzed canonical pathways in which the DEGs were enriched in Hepatic Fibrosis / Hepatic Stellate Cell Activation, Bile Acid Biosynthesis and Tight Junction signaling. After re-annotation against human genome data, the 384 DEGs were pooled together with proteins belonging to hepatitis B pathway to construct a protein-protein interaction network. The combination of decreased expression of liver-specific genes (CYP3A4, CYP1E1, CFI, RELN and GSTA1 et al) with increased expression of hepatocyte-dedifferentiation-associated genes (PLA2G4A and PLCG1) suggested that in vitro culture conditions results in the fading of hepatocyte phenotype in PDHs. The expression of seven DEGs associated with tight junction formation (JAM3, PPP2R2B, PRKAR1B, PPP2R2C, MAGI2, ACTA2 and ACTG2) was up-regulated after short-term culture in vitro, which was attenuated in the presence of DMSO. Those results could shed light on DHBV infection associated molecular events affected by DMSO.
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PMID:Comparative Transcriptomic Analysis of Primary Duck Hepatocytes Provides Insight into Differential Susceptibility to DHBV Infection. 2690 Aug 48


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