2019
Development and Application of a Life-Stage Physiologically Based Pharmacokinetic (PBPK) Model to the Assessment of Internal Dose of Pyrethroids in Humans
Mallick P, Moreau M, Song G, Efremenko A, Pendse S, Creek M, Osimitz T, Hines R, Hinderliter P, Clewell H, Lake B, Yoon M. Development and Application of a Life-Stage Physiologically Based Pharmacokinetic (PBPK) Model to the Assessment of Internal Dose of Pyrethroids in Humans. Toxicological Sciences 2019, 173: 86-99. PMID: 31593217, PMCID: PMC6944222, DOI: 10.1093/toxsci/kfz211.Peer-Reviewed Original ResearchConceptsTarget tissue exposureTissue exposurePharmacokinetic modelLiver blood flowLow internal exposureAge-related sensitivityAge-dependent changesEfficient metabolic clearanceIndividual cytochrome P450Human hepatic metabolismAge-related differencesCis-permethrinHepatic metabolismBlood flowMetabolic clearanceCES enzymesHepatic CLintInternal doseIntrinsic clearanceTarget tissuesInternal exposureClearanceCarboxylesterase enzymesCytochrome P450Vivo extrapolationDevelopmental Expression of the Cytosolic Sulfotransferases in Human Liver
Dubaisi S, Caruso J, Gaedigk R, Vyhlidal C, Smith P, Hines R, Kocarek T, Runge-Morris M. Developmental Expression of the Cytosolic Sulfotransferases in Human Liver. Drug Metabolism And Disposition 2019, 47: dmd.119.086363. PMID: 30885913, PMCID: PMC6505379, DOI: 10.1124/dmd.119.086363.Peer-Reviewed Original ResearchConceptsMRNA levelsLiver specimensHuman liverReverse transcription-quantitative polymerase chain reactionTranscription-quantitative polymerase chain reactionProtein levelsRT-qPCR analysisHuman liver cytosolHuman liver samplesQuantitative polymerase chain reactionCytosolic sulfotransferasesRNA sequencingHepatic sulfotransferasesPolymerase chain reactionDrug eliminationPredominant organInfant liverLiverLiver samplesChain reactionLiver cytosolForeign chemicalsImportant metabolic roleInfantsAdditional findings
2018
The Impact of Scaling Factor Variability on Risk-Relevant Pharmacokinetic Outcomes in Children: A Case Study Using Bromodichloromethane (BDCM)
Kenyon E, Lipscomb J, Pegram R, George B, Hines R. The Impact of Scaling Factor Variability on Risk-Relevant Pharmacokinetic Outcomes in Children: A Case Study Using Bromodichloromethane (BDCM). Toxicological Sciences 2018, 167: 347-359. PMID: 30252107, PMCID: PMC10448349, DOI: 10.1093/toxsci/kfy236.Peer-Reviewed Original ResearchConceptsPharmacokinetic outcomesPK outcomesYounger age groupsDose-response studyBDCM concentrationsLarge inter-individual differencesPediatric populationLiver massBody weightAge groupsMicrosomal contentOral exposure routePharmacokinetic modelDose metricsDrink of waterEnzyme ontogenyOutcome variationEarly childhoodAdult findingsInter-individual differencesOutcomesNeonatesExposure routes
2017
Determination of Human Hepatic CYP2C8 and CYP1A2 Age-Dependent Expression to Support Human Health Risk Assessment for Early Ages
Song G, Sun X, Hines R, McCarver D, Lake B, Osimitz T, Creek M, Clewell H, Yoon M. Determination of Human Hepatic CYP2C8 and CYP1A2 Age-Dependent Expression to Support Human Health Risk Assessment for Early Ages. Drug Metabolism And Disposition 2017, 45: dmd.116.074583. PMID: 28228413, DOI: 10.1124/dmd.116.074583.Peer-Reviewed Original ResearchConceptsCYP2C8 expressionOntogeny dataMonths postnatal ageProtein levelsLiver microsomal samplesAge-dependent expressionMultiple cytochrome P450Weeks' gestationPostnatal agePostnatal dayYoung infantsPostnatal samplesFetal samplesMicrosomal samplesCYP1A2 expressionQuantitative Western blottingPyrethroid metabolismCYP2C8Western blottingHealth risk assessmentHuman health risk assessmentRisk assessmentAgeCarboxylesterase enzymesCytochrome P450
2016
Role of Chromatin Structural Changes in Regulating Human CYP3A Ontogeny
Giebel N, Shadley J, McCarver D, Dorko K, Gramignoli R, Strom S, Yan K, Simpson P, Hines R. Role of Chromatin Structural Changes in Regulating Human CYP3A Ontogeny. Drug Metabolism And Disposition 2016, 44: 1027-1037. PMID: 26921389, PMCID: PMC4931893, DOI: 10.1124/dmd.116.069344.Peer-Reviewed Original ResearchMeSH KeywordsAdultAge FactorsAgedAged, 80 and overBinding SitesChildChild, PreschoolChromatinChromatin Assembly and DisassemblyCytochrome P-450 CYP3AGene Expression Regulation, DevelopmentalGene Expression Regulation, EnzymologicGestational AgeHepatocytesHistonesHumansInfantLiverMiddle AgedNucleic Acid ConformationPromoter Regions, GeneticProtein ConformationStructure-Activity RelationshipTranscription, GeneticAge-Dependent Human Hepatic Carboxylesterase 1 (CES1) and Carboxylesterase 2 (CES2) Postnatal Ontogeny
Hines R, Simpson P, McCarver D. Age-Dependent Human Hepatic Carboxylesterase 1 (CES1) and Carboxylesterase 2 (CES2) Postnatal Ontogeny. Drug Metabolism And Disposition 2016, 44: 959-966. PMID: 26825642, DOI: 10.1124/dmd.115.068957.Peer-Reviewed Original ResearchConceptsHepatic carboxylesterase 1Weeks of ageCarboxylesterase 1CES2 expressionAge groupsYounger age groupsCES1 expressionLiver diseaseAdverse outcomesMetabolic clearancePmol/Older groupOlder individualsWestern blottingLiver samplesWeeksEnvironmental chemicalsPostnatal ontogenyMicrosomal proteinMedian valueAgeCytosolic fractionGroupExpressionSubjects
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
Human Hepatic UGT2B15 Developmental Expression
Divakaran K, Hines R, McCarver D. Human Hepatic UGT2B15 Developmental Expression. Toxicological Sciences 2014, 141: 292-299. PMID: 24980262, PMCID: PMC4271124, DOI: 10.1093/toxsci/kfu126.Peer-Reviewed Original ResearchConceptsUGT2B15 expressionAge groupsHuman hepatic microsomesLate fetal lifeFunctional single nucleotide polymorphismsFetal contentMale genderFetal lifeLate gestationPostnatal samplesLower clearanceOlder individualsWeeks ageHepatic microsomesProtein expressionSingle nucleotide polymorphismsLatter groupImportant drugsMature valuesBisphenol ADevelopmental expressionExpression changesNucleotide polymorphismsGreater rateGroup
2012
Developmental expression of drug metabolizing enzymes: Impact on disposition in neonates and young children
Hines R. Developmental expression of drug metabolizing enzymes: Impact on disposition in neonates and young children. International Journal Of Pharmaceutics 2012, 452: 3-7. PMID: 22766445, DOI: 10.1016/j.ijpharm.2012.05.079.Peer-Reviewed Original ResearchConceptsPerinatal changesDrug dispositionPediatric drug safetyYoung childrenDrug metabolizing enzymesAge-dependent changesSignificant interindividual variationAdverse eventsPharmacogenetic factorsHepatic drugFunctional genetic variantsDrug safetyDrug efficacyMetabolizing enzymesPharmacokinetic modelInterindividual variationEnzyme ontogenyDrugsEnzyme expressionChildrenClass 3Genetic variantsMajor determinantClass 1Current knowledge
2011
Prenatal and Postnatal Expression of Glutathione Transferase ζ 1 in Human Liver and the Roles of Haplotype and Subject Age in Determining Activity with Dichloroacetate
Li W, Gu Y, James M, Hines R, Simpson P, Langaee T, Stacpoole P. Prenatal and Postnatal Expression of Glutathione Transferase ζ 1 in Human Liver and the Roles of Haplotype and Subject Age in Determining Activity with Dichloroacetate. Drug Metabolism And Disposition 2011, 40: 232-239. PMID: 22028318, PMCID: PMC3263939, DOI: 10.1124/dmd.111.041533.Peer-Reviewed Original ResearchMeSH KeywordsAdultAge FactorsAgedAmino Acid SubstitutionAntineoplastic AgentsChildCytoplasmDichloroacetic AcidDrugs, InvestigationalFemaleGene Expression Regulation, DevelopmentalGene Expression Regulation, EnzymologicGlutathione TransferaseHalogenationHumansLiverMaleMiddle AgedMitochondria, LiverPolymorphism, Single NucleotideSubstrate SpecificityYoung AdultConceptsGSTZ1 activityHuman liverProtein expressionAge 74 yearsInfluence of haplotypeAge 7 yearsAge-dependent mannerAge-related increaseRole of haplotypesWeeks' gestationHuman liver developmentNeonatal onsetAge-related differencesLactic acidosisInvestigational drugsSolid tumorsGSTZ1 protein expressionPostnatal expressionSubject ageLevel of expressionFetal liverLiverGSTZ1 expressionExpression levelsTyrosine catabolism
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
Ontogeny of human hepatic cytochromes P450
Hines R. Ontogeny of human hepatic cytochromes P450. Journal Of Biochemical And Molecular Toxicology 2007, 21: 169-175. PMID: 17936930, DOI: 10.1002/jbt.20179.Peer-Reviewed Original ResearchMeSH KeywordsAdolescentAryl Hydrocarbon HydroxylasesChildChild, PreschoolCytochrome P-450 CYP2C19Cytochrome P-450 CYP2C9Cytochrome P-450 CYP2E1Cytochrome P-450 CYP3ACytochrome P-450 Enzyme SystemGene Expression Regulation, DevelopmentalGene Expression Regulation, EnzymologicHumansInfantLiverMixed Function OxygenasesConceptsHuman hepatic cytochrome P450Adverse drug reactionsConsiderable interindividual variabilityHepatic cytochrome P450Cytochrome P450Human liver samplesImportant endogenous functionsWeeks' gestationThird trimesterFirst trimesterDrug reactionsKey cytochrome P450Postnatal onsetPostnatal increaseTherapeutic efficacyInterindividual variabilityQuantitative Western blottingWestern blottingGestationLow levelsLiver samplesProbe substratesOnset of expressionTrimesterThird groupMechanisms 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
Modeling interchild differences in pharmacokinetics on the basis of subject-specific data on physiology and hepatic CYP2E1 levels: A case study with toluene
Nong A, McCarver D, Hines R, Krishnan K. Modeling interchild differences in pharmacokinetics on the basis of subject-specific data on physiology and hepatic CYP2E1 levels: A case study with toluene. Toxicology And Applied Pharmacology 2006, 214: 78-87. PMID: 16464483, DOI: 10.1016/j.taap.2005.12.001.Peer-Reviewed Original ResearchConceptsHepatic CYP2E1 contentCYP2E1 contentLiver volumeHepatic CYP2E1 protein levelsInternal doseHepatic CYP2E1 levelsInterindividual variability factorsPBPK modelVenous blood concentrationsBlood concentration profilesCYP2E1 protein levelsSubgroup of childrenNeonate groupPercentile valuesPpm tolueneBlood concentrationsCYP2E1 levelsHepatic metabolismBody weightLower AUCAge groupsHuman volunteersInterindividual variabilityPharmacokinetic modelIntrinsic clearanceDevelopmental 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
Developmental Expression of Aryl, Estrogen, and Hydroxysteroid Sulfotransferases in Pre- and Postnatal Human Liver
Duanmu Z, Weckle A, Koukouritaki S, Hines R, Falany J, Falany C, Kocarek T, Runge-Morris M. Developmental Expression of Aryl, Estrogen, and Hydroxysteroid Sulfotransferases in Pre- and Postnatal Human Liver. Journal Of Pharmacology And Experimental Therapeutics 2005, 316: 1310-1317. PMID: 16339912, DOI: 10.1124/jpet.105.093633.Peer-Reviewed Original ResearchConceptsHuman liver cytosolImmunoreactive protein levelsHuman liverSULT2A1 expressionPostnatal liver samplesProtein levelsLiver cytosolPostnatal human developmentAdult human liverSemiquantitative Western blot analysisWestern blot analysisThird trimesterPostnatal ageEarly gestationEstrogen inactivationSulfotransferase expressionPostnatal lifeInterindividual variabilityPrenatal periodMale liverDifferent developmental profilesSULT1A1 expressionGestationLiverHydroxysteroid sulfotransferases
2003
Developmental Expression of Human Hepatic CYP2C9 and CYP2C19
Koukouritaki S, Manro J, Marsh S, Stevens J, Rettie A, McCarver D, Hines R. Developmental Expression of Human Hepatic CYP2C9 and CYP2C19. Journal Of Pharmacology And Experimental Therapeutics 2003, 308: 965-974. PMID: 14634042, DOI: 10.1124/jpet.103.060137.Peer-Reviewed Original ResearchDevelopmental Expression of the Major Human Hepatic CYP3A Enzymes
Stevens J, Hines R, Gu C, Koukouritaki S, Manro J, Tandler P, Zaya M. Developmental Expression of the Major Human Hepatic CYP3A Enzymes. Journal Of Pharmacology And Experimental Therapeutics 2003, 307: 573-582. PMID: 12975492, DOI: 10.1124/jpet.103.054841.Peer-Reviewed Original ResearchHuman Hepatic CYP2E1 Expression during Development
Johnsrud E, Koukouritaki S, Divakaran K, Brunengraber L, Hines R, McCarver D. Human Hepatic CYP2E1 Expression during Development. Journal Of Pharmacology And Experimental Therapeutics 2003, 307: 402-407. DOI: 10.1124/jpet.103.053124.Peer-Reviewed Original ResearchConceptsPostnatal ageDays of ageNeonatal samplesOlder infantsCYP2E1 contentHepatic CYP2E1 expressionDays postnatal ageHuman hepatic microsomesHuman fetal liverInfants 31CYP2E1 protein contentGestational ageThird trimesterPostnatal dataGreat intersubject variationCYP2E1 expressionCYP2E1 substratesAge groupsFetal samplesCYP2E1Hepatic microsomesFetal liverInfantsYoung adultsIntersubject variationHuman hepatic CYP2E1 expression during development.
Johnsrud E, Koukouritaki S, Divakaran K, Brunengraber L, Hines R, McCarver D. Human hepatic CYP2E1 expression during development. Journal Of Pharmacology And Experimental Therapeutics 2003, 307: 402-7. PMID: 14500779, DOI: 10.1124/jpet.102.053124.Peer-Reviewed Original ResearchConceptsPostnatal ageNeonatal samplesThird trimesterOlder infantsIncreasing gestational ageDays postnatal ageHuman fetal liverCYP2E1 contentDays of ageImmunodetectable CYP2E1Gestational ageHuman hepatic microsomesSecond-trimesterPostnatal dataFetal liverFetal samplesHepatic CYP2E1 expressionDecreased clearanceInfantsCYP2E1 expressionIntersubject variationCYP2E1CYP2E1 protein contentAge groupsCYP2E1 substrates