Human UDP-glucuronosyltransferase 1A1, which is part of 9-UGT1A proteins encoded by the UGT1 locus, plays a key role in many aspects of normal pathophysiology. Glucuronidation carried out by UGT1A1 is considered the rate limiting step in bilirubin elimination. Over 50% of newborn babies do not process the elimination of bilirubin adequately, due mostly to a lag in developmental expression of UGT1A1. Clinically and in selective genetic deficiencies, severe hyperbilirubinemia leads to bilurubin toxicity, which is classified as kernicterus or the depositing of bilirubin into the brain. Kernicterus most often leas to early neonatal death. To date, there is a paucity of data regarding the mechanisms leading to developmental expression of human UGT1A1 in neonatal children and the mechanisms underlying the onset of kernicterus. To better understand these processes, our laboratory has created humanized mouse models that express all 9-UGT1A genes encoded by the human UGT1 locus. We have determined that expression levels of the UGT1A genes as determined by RNA quantitation in humanized adult mice are concordant with the expression patterns of these genes as determined in human tissues. These observations indicate that normal tissue specific and humoral control of the UGT1 locus in mice is regulated in a fashion similar to what occurs in humans. Interestingly, humanized UGT1 mice develop neonatal hyperbilirubinemia, a condition that returns to normal when the mice are adults. This unique phenotype associated with humanized UGT1 mice will allow us to investigate the regulatory mechanisms associated with developmental control of the UGT1A1 gene and its impact on serum bilirubin. Our preliminary findings indicate that developmental control of serum bilirubin in humanized UGT1 mice is tightly linked to extrahepatic UGT1A1 activity, a new observation that will be exploited in examining the mechanisms leading to control of hyperbilirubinemia. In addition, the accumulation of extreme levels of serum bilirubin by 14 days after birth triggers the accumulation of bilirubin in brain tissue resulting in seizures and death in approximately 10% of the developing mice. The consistency linking hyperbilirubinemia to bilirubin induced seizures and brain toxicity provides us with an animal model to examine the association between developmental regulation of UGT1A1 with the cellular and molecular mechanisms leading to bilirubin induced brain toxicity. Overall, these approaches will allow us to explore in greater detail the pathophysiological, biological, and molecular mechanisms that control the developmental expression of UGT1A1 and its impact on normal bilirubin homeostasis and disease. This knowledge and information will serve as the foundation for examining new therapies and potential treatments to reduce the incidence of bilirubin induced toxicities in humans.
Hyperbilirubinemia or jaundice occurs in children and results from deficient metabolic processes that are uncontrolled during early neonatal development. Although jaundice is a common malady, it often goes unchecked and if not properly managed can lead to central nervous system toxicity and irreversible brain damage. With the development of new humanized animal models, we will be investigating the underlying causes of neonatal hyperbilirubinemia and the mechanisms that lead to bilirubin induced toxicities.
|Kutsuno, Yuki; Itoh, Tomoo; Tukey, Robert H et al. (2014) Glucuronidation of drugs and drug-induced toxicity in humanized UDP-glucuronosyltransferase 1 mice. Drug Metab Dispos 42:1146-52|
|Aoshima, Naoya; Fujie, Yoshiko; Itoh, Tomoo et al. (2014) Glucose induces intestinal human UDP-glucuronosyltransferase (UGT) 1A1 to prevent neonatal hyperbilirubinemia. Sci Rep 4:6343|
|Maruo, Yoshihiro; Morioka, Yoriko; Fujito, Hiroshi et al. (2014) Bilirubin uridine diphosphate-glucuronosyltransferase variation is a genetic basis of breast milk jaundice. J Pediatr 165:36-41.e1|
|Yueh, Mei-Fei; Chen, Shujuan; Nguyen, Nghia et al. (2014) Developmental onset of bilirubin-induced neurotoxicity involves Toll-like receptor 2-dependent signaling in humanized UDP-glucuronosyltransferase1 mice. J Biol Chem 289:4699-709|
|Sumida, Kyohei; Kawana, Makiko; Kouno, Emi et al. (2013) Importance of UDP-glucuronosyltransferase 1A1 expression in skin and its induction by UVB in neonatal hyperbilirubinemia. Mol Pharmacol 84:679-86|
|Chen, Shujuan; Yueh, Mei-Fei; Bigo, Cyril et al. (2013) Intestinal glucuronidation protects against chemotherapy-induced toxicity by irinotecan (CPT-11). Proc Natl Acad Sci U S A 110:19143-8|