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O-11 Maturation of human hepatic membrane transporter proteins in the first four months of life
  1. Van Groen1,
  2. Van De Steeg2,
  3. Van Lipzig2,
  4. Mooij3,
  5. Wortelboer2,
  6. Tibboel1,
  7. Vaes2,
  8. De Wildt4
  1. 1Erasmus MC, ROTTERDAM, Nederland
  2. 2TNO, ZEIST, Netherlands
  3. 3Leiden University Medical Centre – Willem-Alexander Children’s Hospital, LEIDEN, Netherlands
  4. 4Radboudumc, NIJMEGEN, Netherlands

Abstract

Background Hepatic membrane-embedded proteins are involved in trafficking endogenous and exogenous compounds and may influence the pharmacokinetics of drugs. Transporter-specific age-related changes in pro-tein abundance were found in a pilot study (n=24), but now we aimed to elucidate the exact developmental pat-tern of clinically relevant hepatic transporters in a larger cohort of 63 fetuses, preterm and term neonates and in-fants and compare it with adults.

Methods Protein expression of BCRP, BSEP, GLUT1, MCT1, MDR1, MRP1-3, NTCP, OCT1, OATP1B1, OATP1B3, and OATP2B1 was quantified using UPLC-MS/MS, on snap-fro-zen post mortem fetal and infant liver samples and adult surgical liver samples. Protein expression was quantified in isolated crude membrane fractions. Pairwise compar-ison Kruskal-Wallis test was used to analyse a possible age-related difference.

Results Thirty-six fetal [median GA 23.4 weeks (range 15.3–41.3), no PNA], 12 premature neonatal [GA 30.2 weeks (24.9–36.7), PNA 1.0 weeks (0.14–11.4)], 11 term neonatal [GA 40.0 weeks (39.7–41.3), PNA 4.14 weeks (0.29-18.1)], 4 paediatric [PNA 4.13 years (1.08–7.44)] and 8 adult liver samples were studied. Expressions of BCRP, MCT1, OATP1B3, and OATP2B1 were similar in all age groups. MDR1, MRP1, MRP2, MRP3 and OCT1 expressions were low in fetus and high in adults (all p<0.05). Expression of BSEP increased from fetal to term newborn and to adult age (both p<0.01) and of NCTP increased over the whole age range (all p<0.05). GLUT1 and OATP1B1 expressions were high in fetuses and decreased towards newborns age (both p<0.01). GLUT1 expression decreased further in children’s and adult age (both p<0.05).

Conclusion These data further delineate transporter specific changes in protein abundance across the first months of age.

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