Tissue Distribution and Relative Gene Expression of UDP-Glucuronosyltransferases (2B7, 2B15, 2B17) in the Human Fetus

Abstract

UDP-glucuronosyltransferases (UGTs) catalyze phase II conjugation reactions and play an important role in the inactivation and elimination of several drugs. It is well known that the UGT activity in fetal livers is low compared with the UGT activity in adult livers. In this study the mRNA expression levels of the three human subfamilies, 2B7, 2B15, and 2B17, were determined in 20 adult and 60 fetal liver tissue specimens. The expression profile in fetal kidneys (N = 43), adrenals (N = 46), and lungs (N = 37) was also determined. All fetal and adult samples were genotyped for the UGT2B17 deletion polymorphism. Adult liver contained 13-36 times higher levels of UGT2B mRNAs as compared with fetal livers. UGT2B7 was most abundant in fetal lungs and kidneys, whereas UGT2B15 and UGT2B17 were predominant in the liver. There was a significant correlation between UGT2B7 expression levels in lungs and kidneys, whereas for the other UGT2Bs no correlation between the different tissues was observed. Fetuses expressing two UGT2B17 alleles (ins/ins) displayed significantly higher levels of UGT2B17 mRNA compared to ins/del fetuses in lungs, whereas in the other tissues no gene dose-effect was observed.

Application of Physiologically Based Pharmacokinetic Modeling to Predict Acetaminophen Metabolism and Pharmacokinetics in Children

“…This assumption is in line with recent literature findings, where, compared with UGT1A1 and UGT1A9 that had almost no expression, a considerable amount of UGT2B15 mRNA was found in the human fetal liver and the expression level of UGT2B15 mRNA was positively correlated with fetal age. 35,36 These experimental data support the possibility of having an already relatively high expression of UGT2B15 in neonates, as compared with other UGT enzymes. Simulations showed that the UGT1A4 ontogeny profile (75% adult level at birth) sufficiently reflected UGT2B15 activity and was, hence, chosen as a surrogate in our model (Figure 3, table 1, and Supplementary Figure S1 online).…”

Drug Metabolism and Transport During Pregnancy: How Does Drug Disposition Change during Pregnancy and What Are the Mechanisms that Cause Such Changes?

“…In this issue of Drug Metabolism and Disposition, the mRNA expression of UGT2B7, UGT2B15, and UGT2B17 in fetal tissues including fetal liver, lungs, adrenal glands, and kidneys is shown (Ekstrom et al, 2013). Although the mRNA levels were overall lower than those observed in adult human tissues, it is possible that the fetal UGT enzymes do contribute to detoxification of xenobiotics within the fetus.…”

Targeting Inhaled Therapy beyond the Lungs

“…Besides the phase I enzymes discussed above, phase II enzymes such as uridine glucuronosyltransferase, sulfotransferase, glutathione S-transferase and peptidase activity have also been reported [36,37,38,39,40]. Somers et al [34] compared the catalytic activity of both phase I and II enzymes in isolated human lung parenchymal and hepatocyte cells using liquid chromatography-tandem mass spectrometry and found that some evidence for substantial sulfation and deesterification capacity in lung parenchymal cells.…”