Genetic defects of the UDP-glucuronosyltransferase-1 (UGT1) gene that cause familial non-haemolytic unconjugated hyperbilirubinaemias

Clarke, D.W.; Moghrabi, Nabil; Monaghan, Gemma; Cassidy, Andrew J.; Boxer, M.; Hume, Robert; Burchell, Brian

doi:10.1016/s0009-8981(97)00167-8

Cited by 127 publications

(99 citation statements)

References 34 publications

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“…3 For permanent genetic correction of such diseases it is desirable for the therapeutic gene construct to be expressed life-long which is most effectively achieved by stable integration into the target cell genome.…”

Section: Introductionmentioning

confidence: 99%

Tri-iodothyronine and a deleted form of hepatocyte growth factor act synergistically to enhance liver proliferation and enable in vivo retroviral gene transfer via the peripheral venous system

et al. 2000

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Retroviral vectors integrate into the target cell genome in a stable manner and therefore offer the potential for permanent correction of the genetic diseases that affect the liver. These vectors, however, usually require cell division to occur in order to allow provirus entry into the nucleus. We have explored clinically acceptable methods to improve the efficiency of retroviral gene transfer to the liver, which avoid the need for liver damage. Tri-iodothyronine (T3) and recombinant hepatocyte growth factor have previously been used to induce hepatocyte proliferation in rat livers and allow in vivo retroviral gene transfer. We investigated the combined effects of these growth factors, with their differing mechanisms of action, on hepatocyte proliferation in vivo and assessed their effectiveness in priming cells for retroviral

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Section: Introductionmentioning

confidence: 99%

Tri-iodothyronine and a deleted form of hepatocyte growth factor act synergistically to enhance liver proliferation and enable in vivo retroviral gene transfer via the peripheral venous system

et al. 2000

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“…Glucuronidation of this substrate is catalyzed by a specific member of the UDPglucuronosyltransferase family, UGT1A1. [2][3][4][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][7][8][9] and xenobiotic compounds.…”

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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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“…Those that have been reported tend to disrupt important regulatory regions in the promoter, such as the Sp1 binding site (or GC box), 24 and the TATA box. 27 In addition, Guo et al 28 reported that a single nucleotide polymorphism between 2 closely spaced Myc-binding elements (E-boxes) in the promoter/regulatory region of ODC (the ornithine decarbxylase gene) affected the expression of this gene and that individuals homozygous for the A allele are capable of greater ODC expression after environmental exposures. A search for the consensus sequences of cis-acting promoter elements in the putative CDC2L1 promoter sequence revealed a possible location for CAAT box at nt Ϫ49 to nt Ϫ52.…”

Section: Discussionmentioning

confidence: 99%

Analysis of mutations and identification of several polymorphisms in the putative promoter region of the P34^CDC2‐related CDC2L1 gene located at 1P36 in melanoma cell lines and melanoma families

Feng

Shi

Goldstein

et al. 2002

Intl Journal of Cancer

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Genetic defects of the UDP-glucuronosyltransferase-1 (UGT1) gene that cause familial non-haemolytic unconjugated hyperbilirubinaemias

Cited by 127 publications

References 34 publications

Tri-iodothyronine and a deleted form of hepatocyte growth factor act synergistically to enhance liver proliferation and enable in vivo retroviral gene transfer via the peripheral venous system

Tri-iodothyronine and a deleted form of hepatocyte growth factor act synergistically to enhance liver proliferation and enable in vivo retroviral gene transfer via the peripheral venous system

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

Analysis of mutations and identification of several polymorphisms in the putative promoter region of the P34^CDC2‐related CDC2L1 gene located at 1P36 in melanoma cell lines and melanoma families

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Genetic defects of the UDP-glucuronosyltransferase-1 (UGT1) gene that cause familial non-haemolytic unconjugated hyperbilirubinaemias

Cited by 127 publications

References 34 publications

Tri-iodothyronine and a deleted form of hepatocyte growth factor act synergistically to enhance liver proliferation and enable in vivo retroviral gene transfer via the peripheral venous system

Tri-iodothyronine and a deleted form of hepatocyte growth factor act synergistically to enhance liver proliferation and enable in vivo retroviral gene transfer via the peripheral venous system

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

Analysis of mutations and identification of several polymorphisms in the putative promoter region of the P34CDC2‐related CDC2L1 gene located at 1P36 in melanoma cell lines and melanoma families

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Analysis of mutations and identification of several polymorphisms in the putative promoter region of the P34^CDC2‐related CDC2L1 gene located at 1P36 in melanoma cell lines and melanoma families