PT  - JOURNAL ARTICLE
AU  - Mei-Fei Yueh
AU  - Shujuan Chen
AU  - Nghia Nguyen
AU  - Robert H. Tukey
TI  - Developmental, Genetic, Dietary, and Xenobiotic Influences on Neonatal Hyperbilirubinemia
AID  - 10.1124/mol.116.107524
DP  - 2017 May 01
TA  - Molecular Pharmacology
PG  - 545--553
VI  - 91
IP  - 5
4099  - http://molpharm.aspetjournals.org/content/91/5/545.short
4100  - http://molpharm.aspetjournals.org/content/91/5/545.full
SO  - Mol Pharmacol2017 May 01; 91
AB  - Hyperbilirubinemia, caused by the accumulation of unconjugated bilirubin, is one of the most common clinical diagnoses in both premature and term newborns. Owing to the fact that bilirubin is metabolized solely through glucuronidation by UDP-glucuronosyltransferase (UGT) 1A1, it is now known that immaturity of UGT1A1, in combination with the overproduction of bilirubin during the developmental stage, acts as a bottleneck to bilirubin elimination and predisposes the infant to high total serum bilirubin levels. Although neonatal jaundice is mostly benign, excessively high levels of serum bilirubin in a small percentage of newborns can cause bilirubin-induced neurologic dysfunction, potentially leading to permanent brain damage, a condition known as kernicterus. Although a large portion of hyperbilirubinemia cases in newborns are associated with hemolytic diseases, we emphasize here the impaired ability of UGT1A1 to eliminate bilirubin that contributes to hyperbilirubinemia-induced neurotoxicity in the developmental stage. As a series of hereditary UGT1A1 mutations have been identified that are associated with UGT1A1 deficiency, new evidence has verified that delayed expression of UGT1A1 during the early stages of neonatal development is a tightly controlled event involving coordinated intrahepatic and extrahepatic regulation. This review recapitulates the progress that has been made in recent years in understanding the causes and physiopathology of severe hyperbilirubinemia, investigating molecular mechanisms underlying bilirubin-induced encephalopathy, and searching for potential therapies for treating pathologic hyperbilirubinemia. Several animal models have been developed to make it possible to examine bilirubin-induced neurotoxicity from multiple directions. Moreover, environmental factors that may alleviate or worsen the condition of hyperbilirubinemia are discussed.