Proteomic Analysis of the Developmental Trajectory of Human Hepatic Membrane Transporter Proteins in the First Three Months of Life.
Human hepatic membrane-embedded transporter proteins are involved in trafficking endogenous and exogenous substrates. Even though impact of transporters on pharmacokinetics is recognized, little is known on maturation of transporter protein expression levels, especially during early life. We aimed to study the protein expression of 10 transporters in liver tissue from fetuses, infants, and adults. Transporter protein expression levels [ATP-binding cassette transporter (ABC)B1, ABCG2, ABCC2, ABCC3, bile salt efflux pump, glucose transporter 1, monocarboxylate transporter 1, organic anion transporter polypeptide (OATP)1B1, OATP2B1, and organic cation/carnitine transporter 2) were quantified using ultraperformance liquid chromatography tandem mass spectrometry in snap-frozen postmortem fetal, infant, and adult liver samples. Protein expression was quantified in isolated crude membrane fractions. The possible association between postnatal and postmenstrual age versus protein expression was studied. We studied 25 liver samples, as follows: 10 fetal [median gestational age 23.2 wk (range 16.4-37.9)], 12 infantile [gestational age at birth 35.1 wk (27.1-41.0), postnatal age 1 wk (0-11.4)], and 3 adult. The relationship of protein expression with age was explored by comparing age groups. Correlating age within the fetal/infant age group suggested four specific protein expression patterns, as follows: stable, low to high, high to low, and low-high-low. The impact of growth and development on human membrane transporter protein expression is transporter-dependent. The suggested age-related differences in transporter protein expression may aid our understanding of normal growth and development, and also may impact the disposition of substrate drugs in neonates and young infants.
Intensive Care and Department of Pediatric Surgery, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands (M.G.M., J.D.W., B.D.G., D.T., S.N.W.); Department of Biostatistics, Erasmus MC, Rotterdam, The Netherlands (J.R.); Division of Pediatric Gastroenterology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands (B.A.E.K.); TNO, Zeist, The Netherlands (E.v.d.S., H.M.W., W.H.J.V.); and Department of Pharmacology and Toxicology, Radboud University, Nijmegen, The Netherlands (S.N.d.W.).
Miriam G
MG
Mooij
Intensive Care and Department of Pediatric Surgery, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands (M.G.M., J.D.W., B.D.G., D.T., S.N.W.); Department of Biostatistics, Erasmus MC, Rotterdam, The Netherlands (J.R.); Division of Pediatric Gastroenterology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands (B.A.E.K.); TNO, Zeist, The Netherlands (E.v.d.S., H.M.W., W.H.J.V.); and Department of Pharmacology and Toxicology, Radboud University, Nijmegen, The Netherlands (S.N.d.W.).
Evita
E
van de Steeg
Intensive Care and Department of Pediatric Surgery, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands (M.G.M., J.D.W., B.D.G., D.T., S.N.W.); Department of Biostatistics, Erasmus MC, Rotterdam, The Netherlands (J.R.); Division of Pediatric Gastroenterology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands (B.A.E.K.); TNO, Zeist, The Netherlands (E.v.d.S., H.M.W., W.H.J.V.); and Department of Pharmacology and Toxicology, Radboud University, Nijmegen, The Netherlands (S.N.d.W.).
Joost
J
van Rosmalen
Intensive Care and Department of Pediatric Surgery, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands (M.G.M., J.D.W., B.D.G., D.T., S.N.W.); Department of Biostatistics, Erasmus MC, Rotterdam, The Netherlands (J.R.); Division of Pediatric Gastroenterology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands (B.A.E.K.); TNO, Zeist, The Netherlands (E.v.d.S., H.M.W., W.H.J.V.); and Department of Pharmacology and Toxicology, Radboud University, Nijmegen, The Netherlands (S.N.d.W.).
Jonathan D
JD
Windster
Intensive Care and Department of Pediatric Surgery, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands (M.G.M., J.D.W., B.D.G., D.T., S.N.W.); Department of Biostatistics, Erasmus MC, Rotterdam, The Netherlands (J.R.); Division of Pediatric Gastroenterology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands (B.A.E.K.); TNO, Zeist, The Netherlands (E.v.d.S., H.M.W., W.H.J.V.); and Department of Pharmacology and Toxicology, Radboud University, Nijmegen, The Netherlands (S.N.d.W.).
Barbara A E
BA
de Koning
Intensive Care and Department of Pediatric Surgery, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands (M.G.M., J.D.W., B.D.G., D.T., S.N.W.); Department of Biostatistics, Erasmus MC, Rotterdam, The Netherlands (J.R.); Division of Pediatric Gastroenterology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands (B.A.E.K.); TNO, Zeist, The Netherlands (E.v.d.S., H.M.W., W.H.J.V.); and Department of Pharmacology and Toxicology, Radboud University, Nijmegen, The Netherlands (S.N.d.W.).
Wouter H J
WH
Vaes
Intensive Care and Department of Pediatric Surgery, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands (M.G.M., J.D.W., B.D.G., D.T., S.N.W.); Department of Biostatistics, Erasmus MC, Rotterdam, The Netherlands (J.R.); Division of Pediatric Gastroenterology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands (B.A.E.K.); TNO, Zeist, The Netherlands (E.v.d.S., H.M.W., W.H.J.V.); and Department of Pharmacology and Toxicology, Radboud University, Nijmegen, The Netherlands (S.N.d.W.).
Bianca D
BD
van Groen
Intensive Care and Department of Pediatric Surgery, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands (M.G.M., J.D.W., B.D.G., D.T., S.N.W.); Department of Biostatistics, Erasmus MC, Rotterdam, The Netherlands (J.R.); Division of Pediatric Gastroenterology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands (B.A.E.K.); TNO, Zeist, The Netherlands (E.v.d.S., H.M.W., W.H.J.V.); and Department of Pharmacology and Toxicology, Radboud University, Nijmegen, The Netherlands (S.N.d.W.).
Dick
D
Tibboel
Intensive Care and Department of Pediatric Surgery, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands (M.G.M., J.D.W., B.D.G., D.T., S.N.W.); Department of Biostatistics, Erasmus MC, Rotterdam, The Netherlands (J.R.); Division of Pediatric Gastroenterology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands (B.A.E.K.); TNO, Zeist, The Netherlands (E.v.d.S., H.M.W., W.H.J.V.); and Department of Pharmacology and Toxicology, Radboud University, Nijmegen, The Netherlands (S.N.d.W.).
Heleen M
HM
Wortelboer
Intensive Care and Department of Pediatric Surgery, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands (M.G.M., J.D.W., B.D.G., D.T., S.N.W.); Department of Biostatistics, Erasmus MC, Rotterdam, The Netherlands (J.R.); Division of Pediatric Gastroenterology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands (B.A.E.K.); TNO, Zeist, The Netherlands (E.v.d.S., H.M.W., W.H.J.V.); and Department of Pharmacology and Toxicology, Radboud University, Nijmegen, The Netherlands (S.N.d.W.) s.dewildt@erasmusmc.nl.
Saskia N
SN
de Wildt
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000328:Adult; D000367:Age Factors; D000375:Aging / Q000378:metabolism*; D005865:Gestational Age; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008099:Liver / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000378:metabolism*; D027501:Monocarboxylic Acid Transporters / Q000378:metabolism; D000089762:Multidrug Resistance-Associated Protein 2; D027361:Organic Anion Transporters / Q000378:metabolism; D027701:Organic Cation Transport Proteins / Q000378:metabolism; D040901:Proteomics / Q000379:methods*; D027981:Symporters / Q000378:metabolism; D000099233:Monocarboxylate Transport Protein 1
D018528:ATP-Binding Cassette Transporters; D051272:Glucose Transporter Type 1; D026901:Membrane Transport Proteins; D027501:Monocarboxylic Acid Transporters; D000089762:Multidrug Resistance-Associated Protein 2; D027361:Organic Anion Transporters; D027701:Organic Cation Transport Proteins; D027981:Symporters; D000099233:Monocarboxylate Transport Protein 1; C000715087:ABCC2 protein, human; C495677:SLC2A1 protein, human