Analysis of the promoter of human bilirubin UDP-glucuronosyltransferase gene (UGT1*1) in relevance to Gilbert's syndrome

Ueyama, Hisao; Koiwai, Osamu; Soeda, Yoko; Sato, Hiroshi; Satoh, Yuzuru; Ohkubo, Iwao; Doida, Yukio

doi:10.1016/s1386-6346(97)00097-1

Cited by 19 publications

(15 citation statements)

References 22 publications

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“…Other UGT1 isoforms that show reduced drug metabolism have also been reported (Ando et al 2000;Ciotti et al 1997;Guillemette et al 2000a;Adachi et al 1996). Indeed, all the mutant UGTs reported previously showed reduced activity (Yamamoto et al 1998;Ueyama et al 1997). In the present study, however, the variant UGT1A3 showed increased activity, with a relative efficiency of 370% (for W11R-V47A) ( Table 2).…”

Section: Discussionsupporting

confidence: 71%

Six novel UDP-glucuronosyltransferase (UGT1A3) polymorphisms with varying activity

et al. 2004

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Human UDP-glucuronosyltransferase (UGT) is a part of a major excretion pathway for endobiotics and xenobiotics. The UGT family of genes is highly polymorphic, and our aim is to describe novel polymorphisms at the UGT1A3 locus and determine how they alter substrate metabolism and drug reactions. One hundred healthy Japanese adults volunteered for the present study. We sequenced PCR-amplified fragments of the gene directly, and calculated the frequency of the genetic variations detected. To measure variant enzyme activity, we constructed five expression models and used estrone as the substrate in the assays. We identified six novel single nucleotide polymorphisms (SNPs). Of these, four caused amino acid substitutions (17A fi G: Q6R, 31T fi C: W11R, 133C fi T: R45W, and 140T fi C: V47A) and the remaining two were silent (81G fi A: E27E and 447A fi G: A159A). We found five types of alleles having differing SNP combinations: wild type (frequency=0.61), W11R-E27E-A159A (0.10), Q6A-W11R-E27E-A159A (0.055), W11R-E27E-V47A-A159A (0.125), and R45W (0.11). Expression studies found that the variants changed the enzyme efficiencies (K m /V max ) to 121% of the wild type for W11R, 86% for Q6R-W11R, 369% for W11R-V47A, and 70% for R45W. Several UGT 1A3 polymorphisms exist in the Japanese population, having different levels of activity. These polymorphisms are capable of affecting the steady state levels of estrogens, and may increase sensitivity to adverse drug effects.

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Section: Discussionsupporting

confidence: 71%

Six novel UDP-glucuronosyltransferase (UGT1A3) polymorphisms with varying activity

et al. 2004

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“…The proximal Ϫ2.9-kbp promoter of the UGT1A1 gene was cloned 15 ; the sequence of Ϫ3.2 kbp of the promoter was reported previously. 16 To clone a further up-stream sequence of the UGT1A1 gene, primers 5Ј-CTTCATTGGGAAGGA-GCAGGGACACTACATTGAG-3Ј and 5Ј-CCTCTGCCTTGCTCTC-AAAACTCTGGGATAGAC-were designed from the 3Ј-region of immediate up-stream UGT1BP gene (accession number M84126) and the sequence within the 3.2-kbp DNA (accession number D87674), respectively. A 9-kbp DNA was amplified from HepG2 genomic DNA prepared using a QIAamp Tissue Kit (QIAGEN), LA-Taq DNA polymerase (Panvera/Takara, Madison, WI), and these primers.…”

Section: Methodsmentioning

confidence: 99%

“…The UA fragment was generated from pCAT/2.9 kbp, 15 and the UB-fragment was amplified from HepG2 genomic DNA with the primers 5Ј-CATAGTGGTACCACTCTGAATTTTCTGTGCCCA-3Ј and 5Ј-agtccactcgagTTTGAGGCTGCTTCTGCTGTG-3Ј, which were designed based on a reported sequence. 16 U2K, UC, UD, UE, and UF fragments were prepared from the 9-kbp DNA using convenient restriction enzymes. All these fragments were cloned into pGL3TK-firefly luciferase reporter plasmid, 14 and the U2K DNA sequence was determined (GenBank accession number AF313454).…”

Section: Methodsmentioning

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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“…The TATA-box region is the binding site for the transcription factor IID, thereby playing an important role in the initiation of transcription [7]. A variation in this sequence thus reduces the efficiency and accuracy of gene expression, subsequently leading to higher bilirubin levels [7,9,18].…”

Section: Introductionmentioning

confidence: 99%

Analysis of the UDP-glucuronosyltransferase gene in Portuguese patients with a clinical diagnosis of Gilbert and Crigler–Najjar syndromes

Costa

Vieira

Martins

et al. 2006

Blood Cells, Molecules, and Diseases

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We describe the molecular study in a cohort of 120 Portuguese patients with the clinical diagnosis of Gilbert syndrome and in one with the diagnosis of Crigler -Najjar syndrome type II, as well as a prenatal diagnosis of Crigler -Najjar syndrome type I. Among the 120 unrelated patients with Gilbert syndrome, 110 were homozygous for the [TA] . Additional studies in these 9 patients revealed heterozygosity for the c.674T>G, c.488 _ 491dupACCT and c.923G>A mutations, in 1, 1 and 4 patients, respectively. The patient with Crigler -Najjar syndrome type II was a compound heterozygote for [TA]7 and the c.923G>A mutation. The undocumented polymorphisms c.-1126C>T and c.997-82T>C were also detected in the course of this study. Prenatal diagnosis in a family with a boy previously diagnosed as Crigler -Najjar syndrome type I and homozygosity for the c.923G>A mutation revealed that the fetus was unaffected.Homozygosity for the [TA] insertion was found to be the most frequent cause of GS in our population. Identification of further mutations in the UGT1A1 gene was also seen to contribute significantly towards diagnosis. D

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Analysis of the promoter of human bilirubin UDP-glucuronosyltransferase gene (UGT1*1) in relevance to Gilbert's syndrome

Cited by 19 publications

References 22 publications

Six novel UDP-glucuronosyltransferase (UGT1A3) polymorphisms with varying activity

Six novel UDP-glucuronosyltransferase (UGT1A3) polymorphisms with varying activity

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

Analysis of the UDP-glucuronosyltransferase gene in Portuguese patients with a clinical diagnosis of Gilbert and Crigler–Najjar syndromes

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