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Human hepatic UGT2B15 developmental expression.

Karthika Divakaran1, Ronald N Hines1, D Gail McCarver2

  • 1Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin kdivakar@mcw.edu.

Toxicological Sciences : an Official Journal of the Society of Toxicology
|July 2, 2014
PubMed
Summary
This summary is machine-generated.

Human hepatic UGT2B15 protein expression begins in late gestation and increases significantly in early infancy. This developmental pattern may affect the metabolism of drugs and toxicants like BPA in newborns.

Keywords:
SNPUGThepatic liver microsomesontogenysingle nucleotide polymorphismuridine diphosphate glucuronosyltransferase

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Area of Science:

  • Pharmacology
  • Developmental Biology
  • Biochemistry

Background:

  • Human hepatic UGT2B15 (UDP-glucuronosyltransferase 2B15) plays a role in metabolizing drugs and toxicants.
  • Previous knowledge of UGT2B15 developmental expression relied on transcript data, which may not accurately reflect protein levels.
  • Understanding UGT2B15 protein ontogeny is crucial for assessing neonatal drug and toxicant exposure risks.

Purpose of the Study:

  • To quantify UGT2B15 protein expression in human liver microsomes across a wide developmental range.
  • To investigate the impact of a common functional single nucleotide polymorphism (g.253G>T) on UGT2B15 expression.
  • To correlate UGT2B15 protein levels with age, genetic variations, and gender.

Main Methods:

  • Quantification of UGT2B15 protein content in human hepatic microsomes from 236 individuals (8 weeks gestation to 18 years).
  • Analysis of UGT2B15 expression in relation to gestational age, postnatal age, and the presence of the g.253G>T polymorphism.
  • Statistical analysis, including stepwise linear regression, to identify factors associated with UGT2B15 expression.

Main Results:

  • UGT2B15 protein expression initiates in late fetal life (approx. 18% of mature levels) and is similar in neonates and late fetuses.
  • Expression significantly increases in infants aged 3-15 weeks, reaching higher levels than in older children and adults.
  • UGT2B15 expression shows a 31-fold variation overall, with postnatal age, the g.253T allele, and male gender significantly associated with higher expression.

Conclusions:

  • Hepatic UGT2B15 protein expression begins during late gestation, with the most rapid increase occurring in the first few weeks post-birth.
  • Fetal and neonatal individuals may exhibit reduced clearance of UGT2B15 substrates, such as bisphenol A (BPA), compared to older individuals.
  • These developmental changes in UGT2B15 expression have implications for understanding the pharmacokinetics and toxicokinetics of its substrates during early life.