Disorders of Bilirubin Metabolism

Chowdhury, Namita Roy; Chowdhury, Jayanta Roy

doi:10.1002/9780470747919.ch17

Cited by 25 publications

(44 citation statements)

References 209 publications

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“…[72,82,134,170]. This syndrome is an autosomal, recessively inherited disorder characterized by conjugated hyperbilirubinemia (i.e., increased concentration of bilirubin glucuronosides in blood) and deposition of a dark pigment in hepatocytes, so that the liver of an affected individual appears dark blue or black [31, 145,158]. The incidence of Dubin-Johnson syndrome ranges from 1:1,300 among Iranian Jews [152] Fig.…”

Section: Transcriptional and Posttranscriptional Regulation Of Abcc2mentioning

confidence: 99%

The apical conjugate efflux pump ABCC2 (MRP2)

Nies

Keppler

2006

Pflugers Arch - Eur J Physiol

350

255

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ABCC2 is a member of the multidrug resistance protein subfamily localized exclusively to the apical membrane domain of polarized cells, such as hepatocytes, renal proximal tubule epithelia, and intestinal epithelia. This localization supports the function of ABCC2 in the terminal excretion and detoxification of endogenous and xenobiotic organic anions, particularly in the unidirectional efflux of substances conjugated with glutathione, glucuronate, or sulfate, as exemplified by leukotriene C 4 , bilirubin glucuronosides, and some steroid sulfates. The hepatic ABCC2 pump contributes to the driving forces of bile flow. Acquired or hereditary deficiency of ABCC2, the latter known as Dubin-Johnson syndrome in humans, causes an increased concentration of bilirubin glucuronosides in blood because of their efflux from hepatocytes via the basolateral ABCC3, which compensates for the deficiency in ABCC2-mediated apical efflux. In this article we provide an overview on the molecular characteristics of ABCC2 and its expression in various tissues and species. We discuss the transcriptional and posttranscriptional regulation of ABCC2 and review approaches to the functional analysis providing information on its substrate specificity. A comprehensive list of sequence variants in the human ABCC2 gene summarizes predicted and proven functional consequences, including variants leading to Dubin-Johnson syndrome. Keywords

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Section: Transcriptional and Posttranscriptional Regulation Of Abcc2mentioning

confidence: 99%

The apical conjugate efflux pump ABCC2 (MRP2)

Nies

Keppler

2006

Pflugers Arch - Eur J Physiol

350

255

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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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“…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.…”

mentioning

confidence: 99%

“…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.…”

mentioning

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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Disorders of Bilirubin Metabolism

Abstract: These discussions are selected from the weekly staff conferences in the

Cited by 25 publications

References 209 publications

The apical conjugate efflux pump ABCC2 (MRP2)

The apical conjugate efflux pump ABCC2 (MRP2)

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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