Chronic nonhemolytic unconjugated hyperbilirubinemia with glucuronyl transferase deficiency

Arias, Irwin M.; Gartner, Lawrence M.; Cohen, Michael I.; Ezzer, Judith Ben; Levi, A J

doi:10.1016/0002-9343(69)90224-1

Cited by 317 publications

(144 citation statements)

References 58 publications

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“…In fact, Crigler-Najjar syndromes I and II habe been distinguished on the basis of phenobarbital induction of UGT1A1 [45]. CAR/RXR-binding domains were first identified in studies of UGT1A1 regulation [46,47], the only UGT responsible for bilirubin clearance in humans.…”

Section: Car and Pxrmentioning

confidence: 99%

From differential induction of UDP-glucuronosyltransferases in rat liver to characterization of responsible ligand-activated transcription factors, and their multilevel crosstalk in humans

Bock¹

2011

Biochemical Pharmacology

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. From differential induction of UDP-glucuronosyltransferases in rat liver to characterization of responsible ligand-activated transcription factors, and their multilevel crosstalk in humans. Biochemical Pharmacology, Elsevier, 2011, 82 (1) This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64

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Section: Car and Pxrmentioning

confidence: 99%

From differential induction of UDP-glucuronosyltransferases in rat liver to characterization of responsible ligand-activated transcription factors, and their multilevel crosstalk in humans

Bock¹

2011

Biochemical Pharmacology

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“…1 Later, less severe forms of the disease, CN type II and Gilbert's type, were found to be distinct from the CN type I when phenotypes with low levels of glucuronidating activity for the metabolite were found. [6][7][8][9] Phenobarbital (PB) treatment was shown to dramatically reduce the hyperbilirubinemia in an infant with CN type II disease. 10 The chain of these events has led to the practice of treating patients whose hyperbilirubinemia was caused by clinical entities other than CN diseases with PB.…”

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confidence: 99%

The Phenobarbital Response Enhancer Module in the Human Bilirubin Udp–Glucuronosyltransferase Ugt1a1 Gene and Regulation by the Nuclear Receptor Car

2001

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The UDP-glucuronosyltransferase, UGT1A1, is the critical enzyme responsible for detoxification of the potentially neurotoxic bilirubin by conjugating it with glucuronic acid. For decades, phenobarbital (PB) treatment for hyperbilirubinemia has been known to increase expression of the UGT1A1 gene in liver. We have now delineated the PB response activity to a 290-bp distal enhancer sequence (؊3483/؊3194) of the UGT1A1 gene. The enhancer contains 3 putative nuclear receptor motifs, and it was activated by the nuclear orphan receptor, human constitutive active receptor (

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“…[9][10][11] The most intensively studied class of bilirubin UGT inducers has been the barbiturates, which are used clinically for lowering serum unconjugated bilirubin levels in individuals with the type II form of Crigler-Najjar syndrome. 12 More recently, phenobarbital has been shown to be effective for lowering bilirubin in a child with the type I form of Crigler-Najjar who received human hepatocyte cell therapy. 13 The beneficial effect of the barbiturates in these cases is widely assumed to involve induction of bilirubin UGT activity, because phenobarbital increases liver microsomal bilirubin UGT activity in some animals.…”

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confidence: 99%

Expression and inducibility of the human bilirubin UDP-glucuronosyltransferase UGT1A1 in liver and cultured primary hepatocytes: Evidence for both genetic and environmental influences

et al. 1999

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In Crigler-Najjar type II patients and, recently, in CriglerNajjar type I patients treated with human hepatocyte cell therapy, phenobarbital has been used for reducing the serum bilirubin load. Its effect is attributed to induction of the enzyme required for hepatic bilirubin elimination, UDP-glucuronosyltransferase, UGT1A1. This study investigated the expression and inducibility of UGT1A1 in human donor livers and their corresponding primary hepatocyte cultures. Immunoblot analysis using a specific antibody directed against the amino terminal of the human UGT1A1 isoform showed that 5 hepatocyte donors exhibited a G50-fold difference in UGT1A1 level. UGT1A1 protein level correlated strongly with both liver microsomal bilirubin UGT activity and liver UGT1A1 mRNA level (r 2 ‫؍‬ .82 and .72, respectively). Of the 4 patients with the lowest UGT1A1 levels, 3 were homozygotes for the UGT1A1 promoter variant sequence associated with Gilbert's syndrome, and the fourth was a heterozygote. The 3 donors with the highest levels had a history of phenytoin exposure. Hepatocytes isolated from the phenytoin-exposed donors exhibited marked declines in UGT1A1 mRNA levels during culturing. Induction studies using hepatocytes treated for 48 hours with phenobarbital (2 mmol/L), oltipraz (50 mol/L), or 3-methylcholanthrene (2.5 mol/L) revealed UGT1A1-inducing effects of phenobarbital, oltipraz, and, in particular, 3-methylcholanthrene. Our data suggest that both genetic and environmental factors play an important role in the marked interindividual variability in UGT1A1 expression. An understanding of these mechanisms could lead to advances in the pharmacological therapy of life-threatening unconjugated hyperbilirubinemia. (HEPATOLOGY 1999;30:476-484.)Bilirubin is an endogenous waste product generated from the metabolism of heme. 1 At low concentrations (normal range Յ1 mg/dL), it is recognized as being beneficial as a result of its antioxidant properties. However, its accumulation in the serum to high concentrations (Ն20 mg/dL) is associated with serious toxicities, including neurological toxicity (kernicterus) and renal damage. 1 Therefore, the control of bilirubin levels in the body is critical.The major factor controlling the excretion of bilirubin is its rate of glucuronidation in liver. Glucuronidation of this substrate is catalyzed by a specific member of the UDPglucuronosyltransferase family, UGT1A1. 2-5 The level of bilirubin glucuronidation activity (and presumably UGT1A1) in liver is determined by genetic as well as environmental factors. Such factors include exposure to drugs 6-9 and xenobiotic compounds. 9-11 The most intensively studied class of bilirubin UGT inducers has been the barbiturates, which are used clinically for lowering serum unconjugated bilirubin levels in individuals with the type II form of Crigler-Najjar syndrome. 12 More recently, phenobarbital has been shown to be effective for lowering bilirubin in a child with the type I form of Crigler-Najjar who received human hepatocyte cell therapy. 13 The benef...

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Chronic nonhemolytic unconjugated hyperbilirubinemia with glucuronyl transferase deficiency

Cited by 317 publications

References 58 publications

From differential induction of UDP-glucuronosyltransferases in rat liver to characterization of responsible ligand-activated transcription factors, and their multilevel crosstalk in humans

From differential induction of UDP-glucuronosyltransferases in rat liver to characterization of responsible ligand-activated transcription factors, and their multilevel crosstalk in humans

The Phenobarbital Response Enhancer Module in the Human Bilirubin Udp–Glucuronosyltransferase Ugt1a1 Gene and Regulation by the Nuclear Receptor Car

Expression and inducibility of the human bilirubin UDP-glucuronosyltransferase UGT1A1 in liver and cultured primary hepatocytes: Evidence for both genetic and environmental influences

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