Bianca D van Groen1, Evita van de Steeg2, Miriam G Mooij3, Marola M H van Lipzig2, Barbara A E de Koning4, Robert M Verdijk5, Heleen M Wortelboer2, Roger Gaedigk6, Chengpeng Bi6, J Steven Leeder6, Ron H N van Schaik7, Joost van Rosmalen8, Dick Tibboel9, Wouter H Vaes2, Saskia N de Wildt10. 1. Intensive Care and Department of Pediatric Surgery, Erasmus MC-Sophia Children's Hospital, Wytemaweg 80, 3015CN Rotterdam, the Netherlands. Electronic address: b.vangroen@erasmusmc.nl. 2. TNO, Utrechtseweg 48, 3704 HE Zeist, the Netherlands. 3. Department of Pediatrics, Willem-Alexander Children's Hospital, Albinusdreef 2, 2333 ZA Leiden, the Netherlands. 4. Division of Pediatric Gastroenterology, Erasmus MC-Sophia Children's Hospital, Wytemaweg 80, 3015CN Rotterdam, the Netherlands. 5. Department of Pathology, Erasmus MC, 's-Gravendijkwal 230, 3015 CE Rotterdam, the Netherlands. 6. Division of Clinical Pharmacology, Toxicology & Therapeutic Innovation, Department of Pediatrics, Children's Mercy Hospital, 2401 Gillham Rd, Kansas City, MO 64108, USA. 7. Department of Clinical Chemistry, Erasmus MC, University Medical Center, Wytemaweg 80, 3015CN Rotterdam, the Netherlands. 8. Department of Biostatistics, Erasmus MC, Wytemaweg 80, 3015CN Rotterdam, the Netherlands. 9. Intensive Care and Department of Pediatric Surgery, Erasmus MC-Sophia Children's Hospital, Wytemaweg 80, 3015CN Rotterdam, the Netherlands. 10. Intensive Care and Department of Pediatric Surgery, Erasmus MC-Sophia Children's Hospital, Wytemaweg 80, 3015CN Rotterdam, the Netherlands; Department of Pharmacology and Toxicology, Radboud University, Geert Grooteplein 21, 6525 EZ Nijmegen, the Netherlands.
Abstract
BACKGROUND: Hepatic membrane transporters are involved in the transport of many endogenous and exogenous compounds, including drugs. We aimed to study the relation of age with absolute transporter protein expression in a cohort of 62 mainly fetus and newborn samples. METHODS: Protein expressions of BCRP, BSEP, GLUT1, MCT1, MDR1, MRP1, MRP2, MRP3, NTCP, OCT1, OATP1B1, OATP1B3, OATP2B1 and ATP1A1 were quantified with LC-MS/MS in isolated crude membrane fractions of snap-frozen post-mortem fetal and pediatric, and surgical adult liver samples. mRNA expression was quantified using RNA sequencing, and genetic variants with TaqMan assays. We explored relationships between protein expression and age (gestational age [GA], postnatal age [PNA], and postmenstrual age); between protein and mRNA expression; and between protein expression and genotype. RESULTS: We analyzed 36 fetal (median GA 23.4 weeks [range 15.3-41.3]), 12 premature newborn (GA 30.2 weeks [24.9-36.7], PNA 1.0 weeks [0.14-11.4]), 10 term newborn (GA 40.0 weeks [39.7-41.3], PNA 3.9 weeks [0.3-18.1]), 4 pediatric (PNA 4.1 years [1.1-7.4]) and 8 adult liver samples. A relationship with age was found for BCRP, BSEP, GLUT1, MDR1, MRP1, MRP2, MRP3, NTCP, OATP1B1 and OCT1, with the strongest relationship for postmenstrual age. For most transporters mRNA and protein expression were not correlated. No genotype-protein expression relationship was detected. DISCUSSION AND CONCLUSION: Various developmental patterns of protein expression of hepatic transporters emerged in fetuses and newborns up to four months of age. Postmenstrual age was the most robust factor predicting transporter expression in this cohort. Our data fill an important gap in current pediatric transporter ontogeny knowledge.
BACKGROUND: Hepatic membrane transporters are involved in the transport of many endogenous and exogenous compounds, including drugs. We aimed to study the relation of age with absolute transporter protein expression in a cohort of 62 mainly fetus and newborn samples. METHODS: Protein expressions of BCRP, BSEP, GLUT1, MCT1, MDR1, MRP1, MRP2, MRP3, NTCP, OCT1, OATP1B1, OATP1B3, OATP2B1 and ATP1A1 were quantified with LC-MS/MS in isolated crude membrane fractions of snap-frozen post-mortem fetal and pediatric, and surgical adult liver samples. mRNA expression was quantified using RNA sequencing, and genetic variants with TaqMan assays. We explored relationships between protein expression and age (gestational age [GA], postnatal age [PNA], and postmenstrual age); between protein and mRNA expression; and between protein expression and genotype. RESULTS: We analyzed 36 fetal (median GA 23.4 weeks [range 15.3-41.3]), 12 premature newborn (GA 30.2 weeks [24.9-36.7], PNA 1.0 weeks [0.14-11.4]), 10 term newborn (GA 40.0 weeks [39.7-41.3], PNA 3.9 weeks [0.3-18.1]), 4 pediatric (PNA 4.1 years [1.1-7.4]) and 8 adult liver samples. A relationship with age was found for BCRP, BSEP, GLUT1, MDR1, MRP1, MRP2, MRP3, NTCP, OATP1B1 and OCT1, with the strongest relationship for postmenstrual age. For most transporters mRNA and protein expression were not correlated. No genotype-protein expression relationship was detected. DISCUSSION AND CONCLUSION: Various developmental patterns of protein expression of hepatic transporters emerged in fetuses and newborns up to four months of age. Postmenstrual age was the most robust factor predicting transporter expression in this cohort. Our data fill an important gap in current pediatric transporter ontogeny knowledge.
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