0000000000067652

AUTHOR

Celia P. Martinez-jimenez

showing 7 related works from this author

Hepatocyte cell lines: their use, scope and limitations in drug metabolism studies.

2006

Gaining knowledge on the metabolism of a drug, the enzymes involved and its inhibition or induction potential is a necessary step in pharmaceutical development of new compounds. Primary human hepatocytes are considered a cellular model of reference, as they express the majority of drug-metabolising enzymes, respond to enzyme inducers and are capable of generating in vitro a metabolic profile similar to what is found in vivo. However, hepatocytes show phenotypic instability and have a restricted accessibility. Different alternatives have been explored in the past recent years to overcome the limitations of primary hepatocytes. These include immortalisation of adult or fetal human hepatic cel…

PharmacologyCell fusionCell Culture TechniquesDrug Evaluation PreclinicalReproducibility of ResultsGeneral MedicineBiologyToxicologyCell biologyCell LineXenobioticsmedicine.anatomical_structureBiochemistryDownregulation and upregulationCell cultureHepatocytemedicineHepatic stellate cellHepatocytesAnimalsHumansProgenitor cellCellular modelDrug metabolismCell Line TransformedExpert opinion on drug metabolismtoxicology
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Comprehensive analysis of interacting proteins and genome-wide location studies of the Sas3-dependent NuA3 histone acetyltransferase complex

2014

Highlights • We characterise Sas3p and Gcn5p active HAT complexes in WT and deleted TAP-strains. • We confirm that Pdp3p interacts with NuA3, histones and chromatin regulators. • Pdp3p MS-analysis reveals its phosphorylation, ubiquitination and methylation. • Sas3p can substitute Gcn5p in acetylation of histone H3K14 but not of H3K9. • Genome-wide profiling of Sas3p supports its involvement in transcriptional elongation.

nt nucleotidePTM post-translational modificationNuA3 histone acetyltransferase complexChIP-on-chip chromatin immunoprecipitation with genome-wide location arraysBiologyArticleGeneral Biochemistry Genetics and Molecular BiologyChromatin remodelingHistonesHistone H3NuA3 nucleosomal acetyltransferase of histone H3Histone H1Histone H2APdp3TAP–MS strategyHistone codelcsh:QH301-705.5TAP tandem affinity purificationGeneticsRNAPII RNA polymerase IIHistone acetyltransferaseWCE whole cell extractSAGA Spt-Ada-Gcn acetyltransferaseWT wild-typeChromatinYeastCell biologyChIP-on-chiplcsh:Biology (General)Histone methyltransferasebiology.proteinHAT histone acetyltransferaseTSS transcription start siteFEBS Open Bio
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Underexpressed Coactivators PGC1α AND SRC1 Impair Hepatocyte Nuclear Factor 4α Function and Promote Dedifferentiation in Human Hepatoma Cells

2006

Hepatocyte nuclear factor 4alpha (HNF4alpha) plays critical roles during liver development and in the transcriptional regulation of many hepatic genes in adult liver. Here we have demonstrated that in human hepatoma HepG2 cells, HNF4alpha is expressed at levels as high as in human liver but its activity on target genes is very low or absent. We have discovered that the low expression of key coactivators (PGC1alpha, SRC1, SRC2, and PCAF) might account for the lack of function of HNF4alpha in HepG2 cells. Among them, PGC1alpha and SRC1 are the two most important HNF4alpha coactivators as revealed by reporter assays with an Apo-CIII promoter construct. Moreover, the expression of these two coa…

AdultMalemedicine.medical_specialtyCarcinoma HepatocellularDown-RegulationBiologyBiochemistryNuclear Receptor Coactivator 1Cell Line TumorInternal medicinemedicineTranscriptional regulationHomeostasisHumansMolecular BiologyPsychological repressionHeat-Shock ProteinsAgedHistone AcetyltransferasesLiver NeoplasmsCell DifferentiationCell BiologyMiddle AgedPeroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alphaPhenotypeCell biologyNuclear receptor coactivator 1Hepatocyte nuclear factorsEndocrinologyHepatocyte Nuclear Factor 4LiverPCAFCell cultureFemaleHomeostasisTranscription FactorsJournal of Biological Chemistry
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Transcriptional activation of CYP2C9, CYP1A1, and CYP1A2 by hepatocyte nuclear factor 4alpha requires coactivators peroxisomal proliferator activated…

2006

Hepatocyte nuclear factor 4alpha (HNF4alpha) is a key transcription factor for the constitutive expression of cytochromes P450 (P450s) in the liver. However, human hepatoma HepG2 cells show a high level of HNF4alpha but express only marginal P450 levels. We found that the HNF4alpha-mediated P450 transcription in HepG2 is impaired by the low level of coactivators peroxisomal proliferator activated receptor-gamma coactivator 1alpha (PGC1alpha) and steroid receptor coactivator 1 (SRC1). Reporter assays with a chimeric CYP2C9-LUC construct demonstrated that the sole transfection of coactivators induced luciferase activity in HepG2 cells. In HeLa cells however, CYP2C9-LUC activity only significa…

MaleTranscriptional Activationendocrine systemBiologyResponse ElementsTransfectiondigestive systemAdenoviridaeNuclear Receptor Coactivator 1Cytochrome P-450 CYP1A2CoactivatorCytochrome P-450 CYP1A1HumansInsulinTranscription factorCells CulturedHeat-Shock ProteinsCytochrome P-450 CYP2C9Histone AcetyltransferasesPharmacologyTransfectionMiddle AgedMolecular biologyPeroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alphaNuclear receptor coactivator 1Hepatocyte nuclear factorsHepatocyte Nuclear Factor 4Nuclear receptor coactivator 3Nuclear receptor coactivator 2HepatocytesMolecular MedicineFemaleAryl Hydrocarbon HydroxylasesChromatin immunoprecipitationHeLa CellsProtein BindingTranscription FactorsMolecular pharmacology
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Species-specific mechanisms for cholesterol 7alpha-hydroxylase (CYP7A1) regulation by drugs and bile acids.

2005

The gene encoding cholesterol 7alpha-hydroxylase (CYP7A1) is tightly regulated in order to control intrahepatic cholesterol and bile acid levels. Ligands of the xenobiotic-sensing pregnane X receptor inhibit CYP7A1 expression. To retrace the evolution of the molecular mechanisms underlying CYP7A1 inhibition, we used a chicken hepatoma cell system that retains the ability to be induced by phenobarbital and other drugs. Whereas bile acids regulate CYP7A1 via small heterodimer partner and liver receptor homolog-1, mRNA expression of these nuclear receptors is unchanged by xenobiotics. Instead, drugs repress chicken hepatic nuclear factor 4alpha (HNF4alpha) transcript levels concomitant with a …

Receptors Steroidmedicine.drug_classMolecular Sequence DataBiophysicsReceptors Cytoplasmic and NuclearBiologyIn Vitro TechniquesCholesterol 7 alpha-hydroxylaseBiochemistryGene Expression Regulation EnzymologicBile Acids and SaltsMiceSpecies SpecificitymedicineAnimalsHumansRNA MessengerCholesterol 7-alpha-HydroxylaseMolecular BiologyCells CulturedMice KnockoutPregnane X receptorBile acidLiver receptor homolog-1Pregnane X ReceptorPhosphoproteinsRecombinant ProteinsDNA-Binding ProteinsBiochemistryNuclear receptorHepatocyte Nuclear Factor 4PhenobarbitalSmall heterodimer partnerHepatocytesFarnesoid X receptorSignal transductionChickensSignal TransductionTranscription FactorsArchives of biochemistry and biophysics
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Can Hepatoma Cell Lines be Re-differentiated to be Used in Drug Metabolism Studies?

2013

Knowledge of metabolism, enzymes so far involved, and potential enzyme-inhibiting or enzyme-inducing properties of new compounds is a key issue in drug development. Primary cultured hepatocytes, cytochrome P450 (CYP)-engineered cells and hepatoma cell lines are currently being used for this purpose, but only primary cultures can produce a metabolic profile of a drug similar to that found in vivo and can respond to inducers. Because of their limited accessibility, alternatives to replace human hepatocytes are currently being explored, including the immortalisation of hepatocytes by using different strategies (i.e. SV40 T-large antigen, conditionally immortalised hepatocytes, transfection wi…

Carcinoma Hepatocellularbiologybusiness.industryTransgeneCellular differentiationLiver NeoplasmsCytochrome P450Cell DifferentiationGeneral MedicineTransfectionToxicologyGeneral Biochemistry Genetics and Molecular BiologyBiotechnologyCell biologyMedical Laboratory TechnologyCytochrome P-450 Enzyme SystemDrug developmentCell cultureCell Line Tumorbiology.proteinHumansbusinessTranscription factorDrug metabolismTranscription FactorsAlternatives to Laboratory Animals
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Transcriptional regulation and expression of CYP3A4 in hepatocytes.

2007

CYP3A4 is the most abundantly expressed drug-metabolizing P450 enzyme in human liver and contributes to the metabolism of a large number of drugs in use today. CYP3A4 is constitutively expressed in adult hepatocytes but it can also be transcriptionally induced by a variety of structurally diverse xenochemicals. CYP3A4 strongly contributes to the important variability in the therapeutic and toxic effects of drugs owing to the major role it plays in xenobiotic metabolism and the large intra- and inter-individual variability to which it is subjected. The functional examination of up to 13 kb of the CYP3A4 5'-flanking region has revealed that the regulation of this gene is a complex issue, with…

PharmacologyRegulation of gene expressionPregnane X receptorTranscription GeneticClinical BiochemistryDown-RegulationBiologyPharmacologyRegulatory Sequences Nucleic AcidGene Expression Regulation EnzymologicCell biologyDrug developmentNuclear receptorCytochrome P-450 Enzyme SystemLiverRegulatory sequenceTranscriptional regulationHepatocytesAnimalsCytochrome P-450 CYP3AHumansTranscription factorDrug metabolismCurrent drug metabolism
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