title: Reduced expression of UGT1A1 in intestines of humanized UGT1 mice via inactivation of NF-κB leads to hyperbilirubinemia.
abstract: OBJECTIVE
  Bilirubin is a natural and potent antioxidant that accumulates in the blood of newborn children and leads to physiological jaundice. Breastfed infants have higher serum levels of bilirubin than formula-fed infants and are at risk for bilirubin-induced neurological dysfunction (BIND). Clearance of bilirubin requires the expression of uridine diphosphate glucuronosyltransferase (UGT) 1A1; we investigated its role in the association between breast feeding with jaundice in mice.
  
  
  METHODS
  We studied mice in which the original Ugt1 locus was disrupted and replaced with the human UGT1 locus (hUGT1 mice); these mice spontaneously develop neonatal hyperbilirubinemia and BIND. We fed human breast milk or formula to neonatal hUGT1 mice and examined activation of the intestinal xenobiotic receptors pregnane X receptor and constitutive androstane receptor. We also examined inflammatory signaling pathways in mice with disruptions in IκB-kinase-α and IκB kinase-β in the intestinal epithelium.
  
  
  RESULTS
  hUGT1 mice that were fed breast milk developed severe hyperbilirubinemia because of suppression of UGT1A1 in the gastrointestinal tract. Formula-fed hUGT1 mice had lower serum levels of bilirubin, which resulted from induction of UGT1A1 in the gastrointestinal tract. hUGT1/Pxr-null mice did not develop severe hyperbilirubinemia, whereas hUGT1/Car-null mice were susceptible to BIND when they were fed breast milk. Breast milk appeared to suppress intestinal IκB kinase α and β, resulting in inactivation of nuclear factor-κB and loss of expression of UGT1A1, leading to hyperbilirubinemia.
  
  
  CONCLUSIONS
  Breast milk reduces expression of intestinal UGT1A1, which leads to hyperbilirubinemia and BIND; suppression of this gene appears to involve inactivation of nuclear factor-κB. Hyperbilirubinemia can be reduced by activation of pregnane X receptor, constitutive androstane receptor, or nuclear factor-κB.
authors: Laboratory of Environmental Toxicology, Department of Chemistry & Biochemistry, University of California San Diego, La Jolla, California, USA.
authors: Ryoichi
authors: R
authors: Fujiwara
authors: Shujuan
authors: S
authors: Chen
authors: Michael
authors: M
authors: Karin
authors: Robert H
authors: RH
authors: Tukey
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001663:Bilirubin / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D000090702:Constitutive Androstane Receptor; D004195:Disease Models, Animal; D015536:Down-Regulation; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051556:Hyperbilirubinemia, Neonatal / Q000201:enzymology* / Q000235:genetics / Q000517:prevention & control; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D041943:Infant Formula / Q000008:administration & dosage; D007231:Infant, Newborn; D007422:Intestines / Q000201:enzymology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008895:Milk, Human / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D000099148:UGT1A1 Enzyme
chemical_list: D001663:Bilirubin; D015415:Biomarkers; D000090702:Constitutive Androstane Receptor; D014453:Glucuronosyltransferase; D051550:I-kappa B Kinase; D016328:NF-kappa B; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D000099148:UGT1A1 Enzyme; C496564:Chuk protein, mouse; C496562:Ikbkb protein, mouse