2019
Developmental 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 ResearchMeSH KeywordsAdolescentAdultCytosolFemaleHumansInfantInfant, NewbornLiverMaleMiddle AgedRNA, MessengerSulfotransferasesYoung AdultConceptsMRNA 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
Integration of Life-Stage Physiologically Based Pharmacokinetic Models with Adverse Outcome Pathways and Environmental Exposure Models to Screen for Environmental Hazards
El-Masri H, Kleinstreuer N, Hines R, Adams L, Tal T, Isaacs K, Wetmore B, Tan Y. Integration of Life-Stage Physiologically Based Pharmacokinetic Models with Adverse Outcome Pathways and Environmental Exposure Models to Screen for Environmental Hazards. Toxicological Sciences 2016, 152: 230-243. PMID: 27208077, PMCID: PMC5009469, DOI: 10.1093/toxsci/kfw082.Peer-Reviewed Original ResearchConceptsPutative adverse outcome pathwayExposure levelsPharmacokinetic modelAdverse outcome pathwaysPotential exposure levelsFetal blood levelsExternal exposure levelsMaternal exposureBlood levelsExposure modelHigh-throughput toxicity screeningVasculogenesis/angiogenesisOutcome pathwaysPBPK modelExposure estimatesChemical dispositionDevelopmental toxicityPotential exposureVivo extrapolationExposureAdulthood stagesToxicityAssaysEnvironmental exposure modelsPregnancyExpression Patterns of Organic Anion Transporting Polypeptides 1B1 and 1B3 Protein in Human Pediatric Liver
Thomson M, Hines R, Schuetz E, Meibohm B. Expression Patterns of Organic Anion Transporting Polypeptides 1B1 and 1B3 Protein in Human Pediatric Liver. Drug Metabolism And Disposition 2016, 44: 999-1004. PMID: 27098745, PMCID: PMC4931892, DOI: 10.1124/dmd.115.069252.Peer-Reviewed Original ResearchMeSH KeywordsAge FactorsAgingChildChild, PreschoolFemaleGene Expression Regulation, DevelopmentalGene Expression Regulation, EnzymologicGlycosylationHumansInfantInfant, NewbornLiver-Specific Organic Anion Transporter 1MaleProtein Processing, Post-TranslationalSolute Carrier Organic Anion Transporter Family Member 1B3ConceptsYears of ageOrganic anion transporting polypeptide (OATP) 1B1Relative protein expressionAge groupsProtein expressionDrug disposition pathwaysMonths of ageDrug-metabolizing enzymesHigh interindividual variabilityStudied age groupsPolypeptide 1B1Appropriate pharmacotherapyPediatric liverChildren 6Children 2Liver specimensInterindividual variabilityFirst monthDrug transportersWestern blottingDisposition pathwaysPreadolescent periodHigh expressionAge rangeMonthsAge-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
Ontogeny 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
2013
Toll-like receptor genetic variants are associated with Gram-negative infections in VLBW infants
Sampath V, Mulrooney N, Garland J, He J, Patel A, Cohen J, Simpson P, Hines R. Toll-like receptor genetic variants are associated with Gram-negative infections in VLBW infants. Journal Of Perinatology 2013, 33: 772-777. PMID: 23867959, PMCID: PMC4465440, DOI: 10.1038/jp.2013.80.Peer-Reviewed Original ResearchMeSH KeywordsBlack or African AmericanFemaleGenetic Predisposition to DiseaseGenetic VariationGram-Negative Bacterial InfectionsHumansImmunity, InnateInfant, NewbornInfant, PrematureInfant, Premature, DiseasesInfant, Very Low Birth WeightInterleukin-1 Receptor-Associated KinasesLeukocyte CountLogistic ModelsMalePolymorphism, Single NucleotideRisk FactorsToll-Like Receptor 4Toll-Like Receptor 5Toll-Like ReceptorsWhite PeopleConceptsWhite blood cellsToll-like receptorsGram-negative infectionsVLBW infantsBacterial infectionsSingle nucleotide polymorphismsLow birth weight infantsTLR single nucleotide polymorphismsBirth weight infantsElevated WBC countGenetic variantsWeight infantsMulticenter studyTLR4 variantsWBC countFemale infantImmune responseInfantsInfection rateInfectionAlters susceptibilityBlood cellsRegression modelsConfoundersCohort
2012
A TIR domain receptor–associated protein (TIRAP) variant SNP (rs8177374) confers protection against premature birth
Karody V, Le M, Nelson S, Meskin K, Klemm S, Simpson P, Hines R, Sampath V. A TIR domain receptor–associated protein (TIRAP) variant SNP (rs8177374) confers protection against premature birth. Journal Of Perinatology 2012, 33: 341-346. PMID: 23047423, DOI: 10.1038/jp.2012.120.Peer-Reviewed Original ResearchConceptsToll-like receptorsPreterm infantsTerm infantsSingle nucleotide polymorphismsExact testProspective case-control studyTLR single nucleotide polymorphismsPregnancy-induced hypertensionRisk of PTBNuclear factor kappa B1Case-control studyFischer's exact testChi-square testIRAK1 variantsMultiplexed single-base extension assayPlacental abruptionPremature birthNeonatal bloodVariant single nucleotide polymorphismsInfantsCaucasian infantsWeeksModulate susceptibilityAfrican AmericansBirthDevelopmental 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 ResearchMeSH KeywordsChildChild DevelopmentGenetic VariationHumansInfant, NewbornLiverPharmaceutical PreparationsConceptsPerinatal 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
A TLR5 (g.1174C > T) variant that encodes a stop codon (R392X) is associated with bronchopulmonary dysplasia
Sampath V, Garland J, Le M, Patel A, Konduri G, Cohen J, Simpson P, Hines R. A TLR5 (g.1174C > T) variant that encodes a stop codon (R392X) is associated with bronchopulmonary dysplasia. Pediatric Pulmonology 2011, 47: 460-468. PMID: 22058078, DOI: 10.1002/ppul.21568.Peer-Reviewed Original ResearchMeSH KeywordsBronchopulmonary DysplasiaCodon, TerminatorCohort StudiesFemaleGenetic Predisposition to DiseaseGenetic VariationHeterozygoteHumansIncidenceInfant, NewbornInfant, PrematureInfant, Very Low Birth WeightInterleukin-1 Receptor-Associated KinasesMalePilot ProjectsPolymorphism, Single NucleotideProspective StudiesSeverity of Illness IndexToll-Like Receptor 5ConceptsSevere BPDExact testLow birth weight infantsVariant allelesToll-like receptor (TLR) familyBronchopulmonary dysplasia susceptibilityBirth weight infantsPathway single nucleotide polymorphismsTLR pathway genesMulti-center studyFisher's exact testSusceptibility/severityBPD outcomesEpidemiological confoundersBronchopulmonary dysplasiaMultiplexed single-base extension assayPreterm infantsBPD pathogenesisPremature infantsPulmonary homeostasisLower incidencePathogen recognitionBlood samplesClinical informationCurrent evidenceThe NFKB1 (g.-24519delATTG) Variant is Associated with Necrotizing Enterocolitis (NEC) in Premature Infants
Sampath V, Le M, Lane L, Patel A, Cohen J, Simpson P, Garland J, Hines R. The NFKB1 (g.-24519delATTG) Variant is Associated with Necrotizing Enterocolitis (NEC) in Premature Infants. Journal Of Surgical Research 2011, 169: e51-e57. PMID: 21529841, DOI: 10.1016/j.jss.2011.03.017.Peer-Reviewed Original ResearchMeSH KeywordsCase-Control StudiesCohort StudiesEnterocolitis, NecrotizingFemaleGenetic Predisposition to DiseaseHumansIncidenceInfant, NewbornInfant, PrematureInfant, Very Low Birth WeightMaleNF-kappa B p50 SubunitPilot ProjectsPolymorphism, Single NucleotideProspective StudiesRetrospective StudiesSignal TransductionToll-Like ReceptorsConceptsNecrotizing enterocolitisImmune responseBlood samplesSingle nucleotide polymorphismsExact testToll-like receptor pathway genesLow birth weight infantsNFKB1 variantsBirth weight infantsIntestinal immune responseTLR pathway genesFisher's exact testInnate immune responseEnterocolitis (NEC) pathogenesisNEC pathogenesisNEC susceptibilityVLBW infantsWeight infantsCohort studyPreterm infantsPremature infantsTIRAP geneClinical informationGene-environment interactionsInfants
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 Tests
2008
Developmental Changes in Human Liver CYP2D6 Expression
Stevens J, Marsh S, Zaya M, Regina K, Divakaran K, Le M, Hines R. Developmental Changes in Human Liver CYP2D6 Expression. Drug Metabolism And Disposition 2008, 36: 1587-1593. PMID: 18474679, DOI: 10.1124/dmd.108.021873.Peer-Reviewed Original Research
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 dosesPopulation-Based Analysis of Methadone Distribution and Metabolism Using an Age-Dependent Physiologically Based Pharmacokinetic Model
Yang F, Tong X, McCarver D, Hines R, Beard D. Population-Based Analysis of Methadone Distribution and Metabolism Using an Age-Dependent Physiologically Based Pharmacokinetic Model. Journal Of Pharmacokinetics And Pharmacodynamics 2006, 33: 485-518. PMID: 16758333, DOI: 10.1007/s10928-006-9018-0.Peer-Reviewed Original ResearchMeSH KeywordsAdultAge FactorsAnalgesics, OpioidArea Under CurveBiological AvailabilityChild, PreschoolComputer SimulationHumansHydrogen-Ion ConcentrationInfantInfant, NewbornMaleMethadoneMiddle AgedModels, BiologicalMonte Carlo MethodProtein BindingRegression AnalysisStereoisomerismTissue DistributionConceptsInter-individual variabilityPediatric populationPharmacokinetic modelMethadone kineticsPopulation-based analysisPopulation-based pharmacokineticsMetabolism of methadoneMethadone distributionMethadone metabolismMethadone pharmacokineticsOpioid abstinencePediatric patientsClinical effectsPD relationshipBlood concentrationsPlasma concentrationsLimited pharmacokineticsPharmacodynamic dataOrosomucoid concentrationPK parametersPK dataMethadonePharmacokineticsClearance kineticsPBPK modelModeling 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
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 ResearchMeSH KeywordsAge FactorsArylsulfotransferaseBlotting, WesternFemaleFetusHumansInfant, NewbornLiverMaleSulfotransferasesConceptsHuman 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
2004
NTP‐CERHR Expert Panel Report on the reproductive and developmental toxicity of fluoxetine
Hines R, Adams J, Buck G, Faber W, Holson J, Jacobson S, Keszler M, McMartin K, Segraves R, Singer L, Sipes I, Williams P. NTP‐CERHR Expert Panel Report on the reproductive and developmental toxicity of fluoxetine. Birth Defects Research Part B Developmental And Reproductive Toxicology 2004, 71: 193-280. PMID: 15334524, DOI: 10.1002/bdrb.20014.Peer-Reviewed Original Research