Unconjugated Bilirubin and an Increased Proportion of Bilirubin Monoconjugates in the Bile of Patients with Gilbert's Syndrome and Crigler-Najjar Disease

Fevery, Johan; Blanckaert, Norbert; Heirwegh, K. P. M.; Préaux, Anne-Marie; Berthelot, Pièrre

doi:10.1172/jci108877

Cited by 124 publications

(75 citation statements)

References 28 publications

(35 reference statements)

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“…19 While the TATA box of the UGT1A1 gene consists of the A(TA) n TAA sequence, the TA dinucleotide is repeated 6 times in the presumed wild-type gene and 5, 7, or 8 times in "mutant" alleles. [19][20][21] The A(TA) 6 TAA exhibited approximately 4-fold higher transcription activity than the A(AT) 7 TAA in transient transfection assays. The A(TA) n TAA is not a PB response element, because a proximal promoter including this sequence was not capable of activating the transcription in response to PB.…”

Section: Resultsmentioning

confidence: 94%

“…The A(TA) n TAA is not a PB response element, because a proximal promoter including this sequence was not capable of activating the transcription in response to PB. The distal PB response element, gtPBREM, might be able to enhance transcription activity of the weak A(TA) 7 TAA, resulting in induction of the UGT1A1 enzyme to decrease unconjugated bilirubin. In addition, mutation of gtPBREM could become a cause of hyperbiliruminemia, if the enhancer module is regulated by some endogenous factors.…”

Section: Resultsmentioning

confidence: 99%

“…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%

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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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Section: Resultsmentioning

confidence: 94%

Section: Resultsmentioning

confidence: 99%

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confidence: 99%

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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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“…Decreased formation of bilirubin diglucuronide and increased levels of bilirubin monoglucuronide were found in bile in parallel with decreased hepatic UGT activity (35). This disease provides an opportunity to study variation in drug glucuronidation due to the prevalence of the familial disorder within the population.…”

Section: Gilberts Syndromementioning

confidence: 99%

Genetic and environmental factors associated with variation of human xenobiotic glucuronidation and sulfation.

Burchell

Coughtrie

1997

Environ Health Perspect

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Glucuronidation and sulfation are phase 2 metabolic reactions catalyzed by large families of different isoenzymes in man. The textbook view that glucuronidation and sulfation lead to the production of harmless conjugates for simple excretion is not valid. Biologically active and toxic sulfates and glucuronides are produced and lead to adverse drug reactions, including immune hypersensitivity. Considerable variation in xenobiotic conjugation is observed as a result of altered expression of UDP-glucuronosyltransferases (UGTs) and sulfotransferases (STs). Recent cloning and expression of human cDNA encoding UGTs and STs has facilitated characterization of isoform substrate specificity, which has been further validated using specific antibodies and human tissue fractions. The availability of cloned/expressed human enzymes and specific antibodies has enabled the investigation of xenobiotic induction and metabolic disruption leading to adverse responses. Genetic polymorphisms of glucuronidation and sulfation are known to exist although the characterization and assessment of the importance of these variations are hampered by appropriate ethical studies in man with suitable safe model compounds. Genetic analysis has allowed molecular identification of defects in well-known hyperbilirubinemias. However, full characterization of the specific functional roles of human UGTs and STs requires rigorous kinetic and molecular analyses of the role of each enzyme in vivo through the use of specific antibodies and inhibitors. This will lead to the better prediction of variation of xenobiotic glucuronidation and sulfation in man. Environ Health Perspect 1 05(Suppl 4): 739-747 (1997)

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“…Several well-established observations in humansi anid rats in vivo have indlicated that, in the presence of' either a high hepatic bilirubin conicentration or reduce(d mnicrosomial bilirtubin UDP-glucturoniosyltransferase activity, the liver preferenitially formns BMG (9,(12)(13)(14)(15)(16). Theref'ore, we examinied the microsomn-al UDP-gltuctironosyltranisf'erase system of'rat liver to see whether, undi(ler the standard assay conditionis, the pref'erential formncationi of BMGI is related to the uniiphysiologicallv high bilirubfin substrate coincenitrationis used.…”

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confidence: 99%

Mechanism of Bilirubin Diglucuronide Formation in Intact Rats

Blanckaert¹,

Gollan²,

Schmid³

1980

J. Clin. Invest.

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A B S T R A C T Although it is well established that bilirubin monoglucuronide is formed in the liver from bilirubin by a microsomal bilirubin uridine diphosphate (UDP)-glucuronosyltransferase, the subcellular site of conversion of monoglucuronide to diglucuronide and the molecular mechanism involved in diglucuronide synthesis have not been identified. Based on in vitro studies, it has been proposed that two fundamentally different enzyme systems may be involved in diglucuronide synthesis in rat liver: (a) a microsomal UDP-glucuronosyltransferase system requiring UDPglucuronic acid as sugar donor or (b) a transglucuronidation mechanism that involves transfer ofa glucuronosyl residue from one monoglucuronide molecule to another, catalyzed by a liver plasma membrane enzyme. To clarify the mechanism by which bilirubin monoglucuronide is converted in vivo to diglucuronide, three different experimental approaches were used. First, normal rats were injected with either equal amounts of bilirubin-

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Unconjugated Bilirubin and an Increased Proportion of Bilirubin Monoconjugates in the Bile of Patients with Gilbert's Syndrome and Crigler-Najjar Disease

Cited by 124 publications

References 28 publications

The phenobarbital response enhancer module in the human bilirubin UDP-glucuronosyltransferase UGT1A1 gene and regulation by the nuclear receptor CAR

The phenobarbital response enhancer module in the human bilirubin UDP-glucuronosyltransferase UGT1A1 gene and regulation by the nuclear receptor CAR

Genetic and environmental factors associated with variation of human xenobiotic glucuronidation and sulfation.

Mechanism of Bilirubin Diglucuronide Formation in Intact Rats

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