Humanized UGT1 Mice, Regulation of UGT1A1, and the Role of the Intestinal Tract in Neonatal Hyperbilirubinemia and Breast Milk-Induced Jaundice.

Abstract

Neonatal hyperbilirubinemia and the onset of bilirubin encephalopathy and kernicterus result in part from delayed expression of UDP-glucuronosyltransferase 1A1 (UGT1A1) and the ability to metabolize bilirubin. It is generally believed that acute neonatal forms of hyperbilirubinemia develop due to an inability of hepatic UGT1A1 to metabolize efficiently bilirubin for clearance through the hepatobiliary tract. Newly developed mouse models designed to study bilirubin metabolism have led to new insight into the role of the intestinal tract in controlling neonatal hyperbilirubinemia. Humanization of mice with the UGT1 locus (hUGT1 mice) and the UGT1A1 gene provide a unique tool to study the onset of hyperbilirubinemia since the human UGT1A1 gene is developmentally regulated during the neonatal period in hUGT1 mice. A new mechanism outlying developmental expression of intestinal UGT1A1 is presented and its implications in the control of neonatal hyperbilirubinemia discussed. New findings linking breast milk protection against necrotizing enterocolitis and intestinal control of UGT1A1 may help explain the contribution of breast milk toward the development of neonatal hyperbilirubinemia. Our findings outline a new model that includes an active intestinal ROS /IκB kinase/nuclear receptor corepressor 1 loop that can be applied to an understanding of breast milk-induced jaundice.

• Authors: Shujuan Chen, Robert H Tukey
• Journal: Drug metabolism and disposition: the biological fate of chemicals (Drug Metab Dispos) Vol. 46 Issue 11 Pg. 1745-1755 (11 2018) ISSN: 1521-009X [Electronic] United States
• PMID: 30093417 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.

Chemical References

• UGT1A1 enzyme
• Glucuronosyltransferase
• Bilirubin

Topics

• Animals
• Animals, Newborn (metabolism)
• Bilirubin (metabolism)
• Disease Models, Animal
• Female
• Glucuronosyltransferase (metabolism)
• Humans
• Hyperbilirubinemia, Neonatal (metabolism)
• Infant, Newborn
• Intestines (physiology)
• Jaundice (metabolism)
• Liver (metabolism)
• Mice
• Milk, Human (metabolism)