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 factorsDevelopmental 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
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
Age-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
Baseline Chromatin Modification Levels May Predict Interindividual Variability in Ozone-Induced Gene Expression
McCullough S, Bowers E, On D, Morgan D, Dailey L, Hines R, Devlin R, Diaz-Sanchez D. Baseline Chromatin Modification Levels May Predict Interindividual Variability in Ozone-Induced Gene Expression. Toxicological Sciences 2015, 150: 216-224. PMID: 26719369, PMCID: PMC4838038, DOI: 10.1093/toxsci/kfv324.Peer-Reviewed Original ResearchConceptsChromatin modificationsH3 lysine 4 trimethylationSpecific chromatin modificationsChromatin modification statesLysine 4 trimethylationUnmodified H3Human bronchial epithelial cellsModification statesTotal H3H3K27 acetylationCellular signalsGene inductionPrimary human bronchial epithelial cellsKey regulatorGene expressionEpigenetic markersBronchial epithelial cellsTraditional toxicological paradigmModification levelsRelative abundanceAir-liquid interface modelTrimethylationEpithelial cellsH3Specific modificationsOntogeny of plasma proteins, albumin and binding of diazepam, cyclosporine, and deltamethrin
Sethi P, White C, Cummings B, Hines R, Muralidhara S, Bruckner J. Ontogeny of plasma proteins, albumin and binding of diazepam, cyclosporine, and deltamethrin. Pediatric Research 2015, 79: 409-415. PMID: 26571224, DOI: 10.1038/pr.2015.237.Peer-Reviewed Original ResearchConceptsTotal proteinBinding of diazepamUnbound diazepamAlbumin levelsStandard dosesPlasma levelsDrugs/chemicalsPediatric databasePlasma bindingAge groupsMaturational changesAdult levelsCyclosporineDiazepamPlasma albuminThree- to fourfoldPlasma samplesFree drugNeonatesPlasma proteinsPyrethroid insecticidesAge bracketDrugsAlbuminRisk
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
2009
Approaches for Assessing Risks to Sensitive Populations: Lessons Learned from Evaluating Risks in the Pediatric Population
Hines R, Sargent D, Autrup H, Birnbaum L, Brent R, Doerrer N, Hubal E, Juberg D, Laurent C, Luebke R, Olejniczak K, Portier C, Slikker W. Approaches for Assessing Risks to Sensitive Populations: Lessons Learned from Evaluating Risks in the Pediatric Population. Toxicological Sciences 2009, 113: 4-26. PMID: 19770482, PMCID: PMC3469276, DOI: 10.1093/toxsci/kfp217.Peer-Reviewed Original ResearchMeSH KeywordsAdolescentAdultAge FactorsBiomarkersChildChild, PreschoolDose-Response Relationship, DrugEnvironmental ExposureEnvironmental MonitoringGenetic Predisposition to DiseaseGovernment RegulationHealth PolicyHumansInfantInfant, NewbornModels, BiologicalPharmacokineticsPublic HealthRisk AssessmentRisk FactorsToxicity TestsHuman hepatic CYP2B6 developmental expression: The impact of age and genotype
Croom E, Stevens J, Hines R, Wallace A, Hodgson E. Human hepatic CYP2B6 developmental expression: The impact of age and genotype. Biochemical Pharmacology 2009, 78: 184-190. PMID: 19464434, DOI: 10.1016/j.bcp.2009.03.029.Peer-Reviewed Original ResearchConceptsYears of ageMedian ageCYP2B6 expressionCYP2B6 levelsProtein levelsSemi-quantitative Western blottingImpact of ageWeeks' gestationNeonatal periodCYP2B6 protein levelsDonor ageCYP3A7 activityPostnatal dayLiver bankAge groupsFetal samplesAdult levelsPediatric samplesWestern blottingCYP2B6 proteinToxicant metabolismAgeSignificant inductionPercentage of samplesPossible role
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 group
2006
Epirubicin Glucuronidation and UGT2B7 Developmental Expression
Zaya M, Hines R, Stevens J. Epirubicin Glucuronidation and UGT2B7 Developmental Expression. Drug Metabolism And Disposition 2006, 34: 2097-2101. PMID: 16985101, DOI: 10.1124/dmd.106.011387.Peer-Reviewed Original ResearchConceptsPediatric age categoriesPediatric age groupAge categoriesAge groupsLiver microsomesChildhood malignant diseaseMetabolism of epirubicinUse of epirubicinTreatment of adultsYears of ageMonths of ageAge-related changesPediatric patientsAdult age categoriesPostnatal ageCardiac toxicityMalignant diseaseUGT2B7 activityNeonatal samplesPreclinical evaluationUGT2B7 expressionGlucuronidation activityAdult groupGlucuronidationEquivalent dosesModeling 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 clearance
2002
Human 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 timing