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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM100481-02
Application #
8442827
Study Section
Special Emphasis Panel (ZRG1-CB-L (55))
Program Officer
Okita, Richard T
Project Start
2012-03-15
Project End
2015-12-31
Budget Start
2013-01-01
Budget End
2013-12-31
Support Year
2
Fiscal Year
2013
Total Cost
$311,099
Indirect Cost
$110,390
Name
University of California San Diego
Department
Pharmacology
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Chen, Shujuan; Lu, Wenqi; Yueh, Mei-Fei et al. (2017) Intestinal NCoR1, a regulator of epithelial cell maturation, controls neonatal hyperbilirubinemia. Proc Natl Acad Sci U S A 114:E1432-E1440
Yueh, Mei-Fei; Chen, Shujuan; Nguyen, Nghia et al. (2017) Developmental, Genetic, Dietary, and Xenobiotic Influences on Neonatal Hyperbilirubinemia. Mol Pharmacol 91:545-553
Hirashima, Rika; Itoh, Tomoo; Tukey, Robert H et al. (2017) Prediction of drug-induced liver injury using keratinocytes. J Appl Toxicol 37:863-872
Yoda, Emiko; Paszek, Miles; Konopnicki, Camille et al. (2017) Isothiocyanates induce UGT1A1 in humanized UGT1 mice in a CAR dependent fashion that is highly dependent upon oxidative stress. Sci Rep 7:46489
Barateiro, Andreia; Chen, Shujuan; Yueh, Mei-Fei et al. (2016) Reduced Myelination and Increased Glia Reactivity Resulting from Severe Neonatal Hyperbilirubinemia. Mol Pharmacol 89:84-93
Hirashima, Rika; Michimae, Hirofumi; Takemoto, Hiroaki et al. (2016) Induction of the UDP-Glucuronosyltransferase 1A1 during the Perinatal Period Can Cause Neurodevelopmental Toxicity. Mol Pharmacol 90:265-74
Liu, Miao; Chen, Shujuan; Yueh, Mei-Fei et al. (2016) Reduction of p53 by knockdown of the UGT1 locus in colon epithelial cells causes an increase in tumorigenesis. Cell Mol Gastroenterol Hepatol 2:63-76.e5
Touboul, Thomas; Chen, Shujuan; To, Cuong C et al. (2016) Stage-specific regulation of the WNT/?-catenin pathway enhances differentiation of hESCs into hepatocytes. J Hepatol 64:1315-26
Liu, Miao; Chen, Shujuan; Yueh, Mei-Fei et al. (2016) Cadmium and arsenic override NF-?B developmental regulation of the intestinal UGT1A1 gene and control of hyperbilirubinemia. Biochem Pharmacol 110-111:37-46
Yueh, Mei-Fei; Tukey, Robert H (2016) Triclosan: A Widespread Environmental Toxicant with Many Biological Effects. Annu Rev Pharmacol Toxicol 56:251-72

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