Correction of congenital indirect hyperbilirubinemia by small intestinal transplantation

Medley, Mark M.; Hooker, Robert L.; Rabinowitz, Sidney; Holton, Ronald H.; Jaffe, Bernard M.

doi:10.1016/s0002-9610(99)80105-6

Cited by 17 publications

(11 citation statements)

References 33 publications

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“…The programmed increase in small-intestine UGT1A1 correlated well with the decline in serum UCB during the neonatal period. The importance of the small intestine for bilirubin metabolism is supported by in vivo studies showing that transplantation of small intestine from Wister rats to Gunn rats, which are genetically deficient in the UGT1 locus, resulted in a decrease in serum bilirubin levels (23). Combined with these results, our findings support the possibility that the developmental changes in UGT1A1 expression in the small intestine play an important role in bilirubin glucuronidation in humanized UGT1 mice.…”

Section: Discussionsupporting

confidence: 78%

Developmental hyperbilirubinemia and CNS toxicity in mice humanized with theUDP glucuronosyltransferase 1(UGT1) locus

Fujiwara

Nguyen

Chen

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

157

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High levels of unconjugated bilirubin (UCB) in newborn children is associated with a reduction in hepatic UDP glucuronosyltransferase (UGT) 1A1 activity that can lead to CNS toxicity, brain damage, and even death. Little is known regarding those events that lead to UCB accumulation in brain tissue, and therefore, we sought to duplicate this condition in mice. The human UGT1 locus, encoding all 9- UGT1A genes including UGT1A1 , was expressed in Ugt1 −/− mice. Because the most common clinical condition associated with jaundice in adults is Gilbert’s syndrome, which is characterized by an allelic polymorphism in the UGT1A1 promoter, hyperbilirubinemia was monitored in humanized UGT1 mice that expressed either the Gilbert’s UGT1A1*28 allele [ Tg(UGT1 A1*28 )Ugt1 −/− mice] or the normal UGT1A1*1 allele [ Tg(UGT1 A1*1 )Ugt1 −/− mice]. Adult Tg(UGT1 A1*28 )Ugt1 −/− mice expressed elevated levels of total bilirubin (TB) compared with Tg(UGT1 A1*1 )Ugt1 −/− mice, confirming that the promoter polymorphism associated with the UGT1A1*28 allele contributes to hyperbilirubinemia in mice. However, TB accumulated to near toxic levels during neonatal development, a finding that is independent of the Gilbert’s UGT1A1*28 promoter polymorphism. Whereas serum TB levels eventually returned to adult levels, TB clearance in neonatal mice was not associated with hepatic UGT1A1 expression. In ∼10% of the humanized UGT1 mice, peak TB levels culminated in seizures followed by death. UCB deposition in brain tissue and the ensuing seizures were associated with developmental milestones and can be prevented by enhancing regulation of the UGT1A1 gene in neonatal mice.

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Section: Discussionsupporting

confidence: 78%

Developmental hyperbilirubinemia and CNS toxicity in mice humanized with theUDP glucuronosyltransferase 1(UGT1) locus

Fujiwara

Nguyen

Chen

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

157

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“…Any defect in the above mentioned excretory mechanisms can lead to the accumulation of bilirubin in blood causing hepatic jaundice. [25][26][27][28][29][30][31][32][33][34] Overview of hepatic jaundice is given in Figure 1b. 18 …”

Section: Hepatic Jaundicementioning

confidence: 99%

Jaundice: a basic review

et al. 2016

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“…However, there are contradicting findings that a genetic polymorphism of UGT1A1, which causes a significant decrease in the hepatic UGT1A1 expression, did not affect the serum bilirubin levels in human adults26. Transplantation of small intestine from Wister rats to Gunn rats, which are genetically deficient in the UGT1 locus, resulted in a reduction of serum bilirubin levels27. Our recent finding demonstrated that specific induction of UGT1A1 in skin also resulted in a reduction of serum bilirubin28.…”

Section: Discussionmentioning

confidence: 88%

Glucose induces intestinal human UDP-glucuronosyltransferase (UGT) 1A1 to prevent neonatal hyperbilirubinemia

Aoshima

Fujie

Itoh

et al. 2014

Sci Rep

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Inadequate calorie intake or starvation has been suggested as a cause of neonatal jaundice, which can further cause permanent brain damage, kernicterus. This study experimentally investigated whether additional glucose treatments induce the bilirubin-metabolizing enzyme – UDP-glucuronosyltransferase (UGT) 1A1 – to prevent the onset of neonatal hyperbilirubinemia. Neonatal humanized UGT1 (hUGT1) mice physiologically develop jaundice. In this study, UGT1A1 expression levels were determined in the liver and small intestine of neonatal hUGT1 mice that were orally treated with glucose. In the hUGT1 mice, glucose induced UGT1A1 in the small intestine, while it did not affect the expression of UGT1A1 in the liver. UGT1A1 was also induced in the human intestinal Caco-2 cells when the cells were cultured in the presence of glucose. Luciferase assays demonstrated that not only the proximal region (-1300/-7) of the UGT1A1 promoter, but also distal region (-6500/-4050) were responsible for the induction of UGT1A1 in the intestinal cells. Adequate calorie intake would lead to the sufficient expression of UGT1A1 in the small intestine to reduce serum bilirubin levels. Supplemental treatment of newborns with glucose solution can be a convenient and efficient method to treat neonatal jaundice while allowing continuous breastfeeding.

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Correction of congenital indirect hyperbilirubinemia by small intestinal transplantation

Cited by 17 publications

References 33 publications

Developmental hyperbilirubinemia and CNS toxicity in mice humanized with theUDP glucuronosyltransferase 1(UGT1) locus

Developmental hyperbilirubinemia and CNS toxicity in mice humanized with theUDP glucuronosyltransferase 1(UGT1) locus

Jaundice: a basic review

Glucose induces intestinal human UDP-glucuronosyltransferase (UGT) 1A1 to prevent neonatal hyperbilirubinemia

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