2019
A Time-Embedding Network Models the Ontogeny of 23 Hepatic Drug Metabolizing Enzymes
Matlock M, Tambe A, Elliott-Higgins J, Hines R, Miller G, Swamidass S. A Time-Embedding Network Models the Ontogeny of 23 Hepatic Drug Metabolizing Enzymes. Chemical Research In Toxicology 2019, 32: 1707-1721. PMID: 31304741, PMCID: PMC6933754, DOI: 10.1021/acs.chemrestox.9b00223.Peer-Reviewed Original ResearchConceptsAge-dependent changesHepatic Drug Metabolizing EnzymesAdverse drug reactionsValproic acid toxicityDrug metabolizing enzymesDrug metabolism enzymesElimination of drugsPediatric patientsPediatric populationMetabolite exposureDrug reactionsClinical dataElevated riskOverall clearanceDrug toxicityFunction of ageDrug safetyFetal periodMetabolizing enzymesDrug metabolismDrug toxicity risksPotential mechanismsAcid toxicityEnzyme expressionDemographic factors
2015
Oxidative stress-responsive transcription factor NRF2 is not indispensable for the human hepatic Flavin-containing monooxygenase-3 (FMO3) gene expression in HepG2 cells
Rudraiah S, Gu X, Hines R, Manautou J. Oxidative stress-responsive transcription factor NRF2 is not indispensable for the human hepatic Flavin-containing monooxygenase-3 (FMO3) gene expression in HepG2 cells. Toxicology In Vitro 2015, 31: 54-59. PMID: 26616280, PMCID: PMC4695222, DOI: 10.1016/j.tiv.2015.11.016.Peer-Reviewed Original ResearchConceptsGene expressionFlavin-containing monooxygenasesStress-responsive transcription factor Nrf2Stress transcription factorsCytosolic regulatory proteinsHepG2 cellsPromoter-luciferase reporter constructsNrf2 target gene expressionGene regulation studiesCo-transfection studiesTarget gene expressionReporter gene activityHeme oxygenase-1Transcription factor Nrf2Luciferase reporter constructsTranscriptional regulationGene regulationKelch-like ECHGene activityTranscription factorsRegulatory proteinsRegulatory pathwaysReporter constructsExpression vectorRegulation studies
2014
Tolerance to Acetaminophen Hepatotoxicity in the Mouse Model of Autoprotection Is Associated with Induction of Flavin-Containing Monooxygenase-3 (FMO3) in Hepatocytes
Rudraiah S, Rohrer P, Gurevich I, Goedken M, Rasmussen T, Hines R, Manautou J. Tolerance to Acetaminophen Hepatotoxicity in the Mouse Model of Autoprotection Is Associated with Induction of Flavin-Containing Monooxygenase-3 (FMO3) in Hepatocytes. Toxicological Sciences 2014, 141: 263-277. PMID: 24973094, PMCID: PMC4271123, DOI: 10.1093/toxsci/kfu124.Peer-Reviewed Original ResearchConceptsMale C57BL/6J miceAPAP hepatotoxicityFlavin-Containing Monooxygenase 3Protein expressionC57BL/6J miceFemale miceMouse modelMRNA levelsFirst time inductionNovel protective functionSingle doseAPAP treatmentMale miceAPAP cytotoxicityAcetaminophen pretreatmentHepatotoxic doseHigh doseAcetaminophen hepatotoxicityHepatotoxicityMice resultsCell line clonesMRNA expressionFMO3 expressionMiceAPAP
2008
Differential regulation of human hepatic flavin containing monooxygenase 3 (FMO3) by CCAAT/enhancer-binding protein β (C/EBPβ) liver inhibitory and liver activating proteins
Klick D, Shadley J, Hines R. Differential regulation of human hepatic flavin containing monooxygenase 3 (FMO3) by CCAAT/enhancer-binding protein β (C/EBPβ) liver inhibitory and liver activating proteins. Biochemical Pharmacology 2008, 76: 268-278. PMID: 18555208, DOI: 10.1016/j.bcp.2008.05.002.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedBase SequenceCCAAT-Enhancer-Binding Protein-betaCell Line, TumorCells, CulturedDNAEmbryo, MammalianFemaleHepatocyte Nuclear Factor 3-betaHepatocytesHumansInfantLiverMaleMiddle AgedMolecular Sequence DataMutagenesis, Site-DirectedOxygenasesPromoter Regions, GeneticProtein Structure, TertiarySequence AlignmentSequence Analysis, DNAConceptsNuclear proteinsLiver nuclear proteinsSpecific DNA/protein interactionsPromoter activityDNA-protein binding studiesDNA/protein interactionsDNA-protein interactionsTransient expression experimentsCell nuclear proteinsDNA methylase inhibitorCCAAT enhancer-binding proteinGene regulation studiesEnhancer-binding proteinNuclear protein extractsOxidative xenobiotic metabolismHepG2 cellsFMO3 expressionTranscriptional machineryChromatin immunoprecipitationProtein interactionsPromoter functionExpression experimentsMethylase inhibitorTransient expressionDNA hypermethylation
2007
Mechanisms Regulating Human FMO3 Transcription
Klick D, Hines R. Mechanisms Regulating Human FMO3 Transcription. Drug Metabolism Reviews 2007, 39: 419-442. PMID: 17786630, DOI: 10.1080/03602530701498612.Peer-Reviewed Original ResearchConceptsGC-box binding proteinsHepG2 cellsPromoter characterizationLiver nuclear proteinsNuclear proteinsTransient expressionFMO enzymesDevelopmental expressionBinding proteinTranscriptionAdult regulationProteinSpecific mechanismsEnzymeExpressionCellsNFYMajor roleYY1USF1Oxidative drugsHeterodimersMonooxygenasesReporterIsoforms
2006
Identification and Functional Analysis of Common Human Flavin-Containing Monooxygenase 3 Genetic Variants
Koukouritaki S, Poch M, Henderson M, Siddens L, Krueger S, VanDyke J, Williams D, Pajewski N, Wang T, Hines R. Identification and Functional Analysis of Common Human Flavin-Containing Monooxygenase 3 Genetic Variants. Journal Of Pharmacology And Experimental Therapeutics 2006, 320: 266-273. PMID: 17050781, DOI: 10.1124/jpet.106.112268.Peer-Reviewed Original ResearchEnzyme-Mediated Protein Haptenation of Dapsone and Sulfamethoxazole in Human Keratinocytes: II. Expression and Role of Flavin-Containing Monooxygenases and Peroxidases
Vyas P, Roychowdhury S, Koukouritaki S, Hines R, Krueger S, Williams D, Nauseef W, Svensson C. Enzyme-Mediated Protein Haptenation of Dapsone and Sulfamethoxazole in Human Keratinocytes: II. Expression and Role of Flavin-Containing Monooxygenases and Peroxidases. Journal Of Pharmacology And Experimental Therapeutics 2006, 319: 497-505. PMID: 16857727, DOI: 10.1124/jpet.106.105874.Peer-Reviewed Original ResearchDevelopmental and tissue-specific expression of human flavin-containing monooxygenases 1 and 3
Hines R. Developmental and tissue-specific expression of human flavin-containing monooxygenases 1 and 3. Expert Opinion On Drug Metabolism & Toxicology 2006, 2: 41-49. PMID: 16863467, DOI: 10.1517/17425255.2.1.41.Peer-Reviewed Original ResearchConceptsAnimal modelsMost animal modelsHuman fetal liverAdult human liverAdverse reactionsToxicant dispositionTherapeutic efficacyDrug metabolismHuman liverFetal liverToxicant metabolismDrugsEnzyme expressionCytochrome P450-dependent monooxygenasesLiverP450-dependent monooxygenasesFamily membersFMO enzymesRecent studiesMonooxygenases 1FMO3MetabolismExpression patternsExpression
2005
Discovery of Novel Flavin-Containing Monooxygenase 3 (FMO3) Single Nucleotide Polymorphisms and Functional Analysis of Upstream Haplotype Variants
Koukouritaki S, Poch M, Cabacungan E, McCarver D, Hines R. Discovery of Novel Flavin-Containing Monooxygenase 3 (FMO3) Single Nucleotide Polymorphisms and Functional Analysis of Upstream Haplotype Variants. Molecular Pharmacology 2005, 68: 383-392. PMID: 15858076, DOI: 10.1124/mol.105.012062.Peer-Reviewed Original ResearchConceptsFlavin-containing monooxygenasesFunctional analysisSingle nucleotide polymorphism (SNP) discoveryMembrane interaction domainHaplotype variantsSite-directed mutagenesisConsensus splice sitesFMO3 expressionUpstream SNPsGene functionPolymorphism discoveryNear complete lossRossmann foldFAD bindingInteraction domainSingle nucleotide polymorphismsRegion haplotypesHaplotype 8Exon SNPsFMO enzymesPromoter activityIntron SNPSequence analysisSNP frequenciesLuciferase constructHaplotype and functional analysis of four flavin-containing monooxygenase isoform 2 (FMO2) polymorphisms in Hispanics
Krueger S, Siddens L, Henderson M, Andreasen E, Tanguay R, Pereira C, Cabacungan E, Hines R, Ardlie K, Williams D. Haplotype and functional analysis of four flavin-containing monooxygenase isoform 2 (FMO2) polymorphisms in Hispanics. Pharmacogenetics And Genomics 2005, 15: 245-256. PMID: 15864117, PMCID: PMC1351039, DOI: 10.1097/01213011-200504000-00008.Peer-Reviewed Original ResearchMeSH KeywordsAllelesAntithyroid AgentsDNA PrimersDNA, ComplementaryEthylenethioureaGenetic VectorsGenotypeHaplotypesHispanic or LatinoHomozygoteHumansMethimazoleMutagenesis, Site-DirectedMutationOxygenasesPharmacogeneticsPolymerase Chain ReactionPolymorphism, GeneticPolymorphism, Single NucleotidePolymorphism, Single-Stranded ConformationalTemperatureConceptsSingle nucleotide polymorphismsInactive proteinProtein variantsSingle-strand conformation polymorphismFunctional analysisActive proteinStrand conformation polymorphismNucleotide polymorphismsFunctional impactProteinAllelesHaplotype determinationConformation polymorphismMajor alleleHaplotypesPolymorphismFMO2Minor alleleFlavinVariants
2004
DIFFERENCES IN FMO2*1 ALLELIC FREQUENCY BETWEEN HISPANICS OF PUERTO RICAN AND MEXICAN DESCENT
Krueger S, Siddens L, Martin S, Yu Z, Pereira C, Cabacungan E, Hines R, Ardlie K, Raucy J, Williams D. DIFFERENCES IN FMO2*1 ALLELIC FREQUENCY BETWEEN HISPANICS OF PUERTO RICAN AND MEXICAN DESCENT. Drug Metabolism And Disposition 2004, 32: 1337-1340. PMID: 15355885, DOI: 10.1124/dmd.104.001099.Peer-Reviewed Original Research
2003
Genetic Variability at the Human FMO1 Locus: Significance of a Basal Promoter Yin Yang 1 Element Polymorphism (FMO1*6)
Hines R, Luo Z, Hopp K, Cabacungan E, Koukouritaki S, McCarver D. Genetic Variability at the Human FMO1 Locus: Significance of a Basal Promoter Yin Yang 1 Element Polymorphism (FMO1*6). Journal Of Pharmacology And Experimental Therapeutics 2003, 306: 1210-1218. PMID: 12829732, DOI: 10.1124/jpet.103.053686.Peer-Reviewed Original ResearchConceptsSingle nucleotide polymorphismsFlavin-containing monooxygenasesGenetic variabilityIntron 1 splice donor siteElectrophoretic mobility shift assaysYin Yang 1 (YY1) transcription factorTransient expression assaysCore binding sequenceATG start codonMobility shift assaysSplice donor siteCommon single nucleotide polymorphismsYY1 bindingStructural geneTranscription factorsStart codonShift assaysExonic sequencesChromosome 1q23Binding sequenceExpression assaysPromoter activityVariety of toxicantsBase pairsNucleotide polymorphismsBiochemical and clinical aspects of the human flavin-containing monooxygenase form 3 (FMO3) related to trimethylaminuria.
Cashman J, Camp K, Fakharzadeh S, Fennessey P, Hines R, Mamer O, Mitchell S, Nguyen G, Schlenk D, Smith R, Tjoa S, Williams D, Yannicelli S. Biochemical and clinical aspects of the human flavin-containing monooxygenase form 3 (FMO3) related to trimethylaminuria. Current Drug Metabolism 2003, 4: 151-70. PMID: 12678693, DOI: 10.2174/1389200033489505.Peer-Reviewed Original ResearchConceptsMonooxygenase form 3Rare metabolic disorderFoul body odorPrimary genetic formsTreatment of individualsNutritional supportVitamin supplementationPlasma cholineTreatment strategiesClinical aspectsClinical basisDrug treatmentMetabolic disordersChildhood formUrinary trimethylamineBody secretionsAbnormal amountsGenetic formsDisease statesDietary sourcesTrimethylamine N-oxideTrimethylaminuriaVariant formDisordersBody odor
2002
Alternative Processing of the Human FMO6 Gene Renders Transcripts Incapable of Encoding a Functional Flavin-Containing Monooxygenase
Hines R, Hopp K, Franco J, Saeian K, Begun F. Alternative Processing of the Human FMO6 Gene Renders Transcripts Incapable of Encoding a Functional Flavin-Containing Monooxygenase. Molecular Pharmacology 2002, 62: 320-325. PMID: 12130684, DOI: 10.1124/mol.62.2.320.Peer-Reviewed Original ResearchHuman Hepatic Flavin-Containing Monooxygenases 1 (FMO1) and 3 (FMO3) Developmental Expression
Koukouritaki S, Simpson P, Yeung C, Rettie A, Hines R. Human Hepatic Flavin-Containing Monooxygenases 1 (FMO1) and 3 (FMO3) Developmental Expression. Pediatric Research 2002, 51: 236-243. PMID: 11809920, DOI: 10.1203/00006450-200202000-00018.Peer-Reviewed Original ResearchConceptsFlavin-containing monooxygenasesExpression patternsSpecies-specific expression patternsFMO3 expressionTemporal expression patternsMajor adult isoformFMO genesPotential control mechanismsDevelopmental expressionProtein levelsAdult isoformsWestern blottingExpressionEmbryosNumerous therapeuticsIsoformsMonooxygenases 1Most individualsFMO3Microsomal fractionHuman liver samplesIntermediate levelsControl mechanismsGenesPrecise timingGENETIC POLYMORPHISMS OF FLAVIN-CONTAINING MONOOXYGENASE (FMO)
Krueger S, Williams D, Yueh M, Martin S, Hines R, Raucy J, Dolphin C, Shephard E, Phillips I. GENETIC POLYMORPHISMS OF FLAVIN-CONTAINING MONOOXYGENASE (FMO). Drug Metabolism Reviews 2002, 34: 523-532. PMID: 12214664, DOI: 10.1081/dmr-120005653.Peer-Reviewed Original ResearchConceptsFlavin-Containing MonooxygenaseAdult human liverPercent of individualsPlethora of drugsTrimethylamine N-oxygenationDrug metabolismHuman liverGenetic polymorphismsHispanic descentPremature stop codonPolymorphic expressionLungPreliminary evidenceFunctional FMO2African descentXenobiotic toxicityMammalian flavinN-oxygenationFMO2TrimethylaminuriaEthylene thioureaPolymorphismAllelesPatientsExpressionEthnic differences in allelic frequency of two flavin-containing monooxygenase 3 (FMO3) polymorphisms: linkage and effects on in vivo and in vitro FMO activities
Park C, Kang J, Chung W, Yi H, Pie J, Park D, Hines R, McCarver D, Cha Y. Ethnic differences in allelic frequency of two flavin-containing monooxygenase 3 (FMO3) polymorphisms: linkage and effects on in vivo and in vitro FMO activities. Pharmacogenetics And Genomics 2002, 12: 77-80. PMID: 11773868, DOI: 10.1097/00008571-200201000-00011.Peer-Reviewed Original Research
2001
Regulation of Flavin-Containing Monooxygenase 1 Expression by Ying Yang 1 and Hepatic Nuclear Factors 1 and 4
Luo Z, Hines R. Regulation of Flavin-Containing Monooxygenase 1 Expression by Ying Yang 1 and Hepatic Nuclear Factors 1 and 4. Molecular Pharmacology 2001, 60: 1421-1430. PMID: 11723251, DOI: 10.1124/mol.60.6.1421.Peer-Reviewed Original ResearchAnimalsBase SequenceDNA-Binding ProteinsEnhancer Elements, GeneticErythroid-Specific DNA-Binding FactorsGene Expression Regulation, EnzymologicHepatocyte Nuclear Factor 1Hepatocyte Nuclear Factor 1-alphaHepatocyte Nuclear Factor 1-betaHumansMolecular Sequence DataNuclear ProteinsOxygenasesPromoter Regions, GeneticRabbitsSequence Homology, Nucleic AcidTranscription FactorsTransfectionTumor Cells, CulturedYY1 Transcription Factor
2000
Ethnic Differences in Human Flavin-Containing Monooxygenase 2 (FMO2) Polymorphisms: Detection of Expressed Protein in African-Americans
Whetstine J, Yueh M, Hopp K, McCarver D, Williams D, Park C, Kang J, Cha Y, Dolphin C, Shephard E, Phillips I, Hines R. Ethnic Differences in Human Flavin-Containing Monooxygenase 2 (FMO2) Polymorphisms: Detection of Expressed Protein in African-Americans. Toxicology And Applied Pharmacology 2000, 168: 216-224. PMID: 11042094, DOI: 10.1006/taap.2000.9050.Peer-Reviewed Original Research
1999
Flavin‐containing monooxygenase isoform 2: Developmental expression in fetal and neonatal rabbit lung
Larsen‐Su S, Krueger S, Yueh M, Lee M, Shehin S, Hines R, Williams D. Flavin‐containing monooxygenase isoform 2: Developmental expression in fetal and neonatal rabbit lung. Journal Of Biochemical And Molecular Toxicology 1999, 13: 187-193. PMID: 10098904, DOI: 10.1002/(sici)1099-0461(1999)13:3/4<187::aid-jbt9>3.0.co;2-6.Peer-Reviewed Original ResearchConceptsEarly developmental appearanceRabbit lungsNeonatal rabbit lungConstitutive cytochrome P450Developmental appearanceNeonatal lungToxic insultsLungMonooxygenase isoformsNumerous xenobioticsForeign chemicalsMonooxygenase functionCytochrome P450Major isoformsTissue-specific fashionDevelopmental expressionMammalian flavinIsoform 2Expression patternsIsoformsFMO2Individual isoformsNeonatesFetuses