Variability and Function of Family 1 Uridine-5′-Diphosphate Glucuronosyltransferases (UGT1A)

Strassburg, Christian P.; Kalthoff, Sandra; Ehmer, Ursula

doi:10.1080/10408360802374624

Cited by 62 publications

(51 citation statements)

References 194 publications

(169 reference statements)

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“…This enzyme is mainly expressed in the liver and has an important role in the glucuronidation of bilirubin, 17β-estradiol [2], some therapeutic drugs [3] and mutagenic xenobiotics [4]. Absence or severe reductions of UGT1A1 activity are associated with CriglerNajjar syndrome type I [5] and type II [6], respectively.…”

Section: Introductionmentioning

confidence: 99%

“…The UGT1A1 gene locus has been mapped to chromosome 2q37 [8], has nine potential functional exon 1 sequences at the 5′ end of the gene that can be joint with the constant exons 2-5 at the 3′ end [3]. One of the most common genetic variants is a repeat polymorphism in the TATA box region of the UGT1A1 promoter.…”

Section: Introductionmentioning

confidence: 99%

“…Homozygosity for the TA duplication was considered as the main cause of GS in Caucasian population [9,10], and justifies some of the inter-individual variations in bilirubin levels, even in the normal population [12]. However, individuals with normal bilirubin levels and without clinical diagnosis of GS can also show this polymorphism in homozygosity [3,9]. Thus, this polymorphism appears to be necessary for GS, but it is not sufficient for the complete manifestation of the disease [12].…”

Section: Introductionmentioning

confidence: 99%

“…In Caucasian and Japanese patients this polymorphism was described and referred to be in linkage disequilibrium with the TA duplication (c.−41_ −40dupTA) [13][14][15][16]. In the last years more than 100 single nucleotide polymorphisms (SNPs) have also been described within the UGT1A1 gene [3].…”

Section: Introductionmentioning

confidence: 99%

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Impact of UGT1A1 gene variants on total bilirubin levels in Gilbert syndrome patients and in healthy subjects

Rodrigues¹,

Vieira²,

Santos³

et al. 2012

Blood Cells, Molecules, and Diseases

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The Gilbert syndrome is a benign form of unconjugated hyperbilirubinemia, mainly associated with alterations in UGT1A1 gene. This work investigated the effect of UGT1A1 variants on total bilirubin levels in Gilbert patients (n = 45) and healthy controls (n = 161). Total bilirubin levels were determined using a colorimetric method; molecular analysis of exons 1-5 and two UGT1A1 promoter regions were performed by direct sequencing and automatic analysis of fragments. Five in silico methods predicted the effect of new identified variants. A significant different allelic distribution, in Gilbert patients and in controls, was found for two promoter polymorphisms. Among patients, 82.2% were homozygous and 17.8% heterozygous for the c.−41_−40dupTA allele; in control group, 9.9% were homozygous and 43.5% heterozygous for this promoter variant, while 46.6% (n = 75) presented the [A(TA) 6 TAA]. For the T>G transition at c.−3279 promoter region, in patients, 86.7% were homozygous and 13.3% heterozygous; in control group, 33.5% were homozygous for the wild type allele, 44.1% were heterozygous and 22.4% homozygous for the mutated allele. The two polymorphisms were in Hardy-Weinberg equilibrium in both groups. Sequencing of UGT1A1 coding region identified nine novel variants, five in patients and four in controls. In silico analysis of these amino acids replacements predicted four of them as benign and three as damaging.In conclusion, we demonstrated that total bilirubin levels are mainly determined by the TA duplication in the TATA-box promoter and by the c.−3279T>G variant. Alterations in the UGT1A1 coding region seem to be associated with increased bilirubin levels, and, therefore, with Gilbert syndrome.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Impact of UGT1A1 gene variants on total bilirubin levels in Gilbert syndrome patients and in healthy subjects

Rodrigues¹,

Vieira²,

Santos³

et al. 2012

Blood Cells, Molecules, and Diseases

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“…Glucuronidation leads to biologically inactive glucuronides in most instances. The human UGT1A enzyme family encoded on chromosome 2 comprises nine members (UGT1A1, UGT1A3, UGT1A4, UGT1A5, UGT1A6, UGT1A7, UGT1A8, UGT1A9, and UGT1A10) (10). The proximal 1 kb of the UGT1A8 -10 promoters are highly similar, displaying Ͼ75% of sequence identity (11).…”

mentioning

confidence: 99%

Interaction between Oxidative Stress Sensor Nrf2 and Xenobiotic-activated Aryl Hydrocarbon Receptor in the Regulation of the Human Phase II Detoxifying UDP-glucuronosyltransferase 1A10

Kalthoff

Ehmer

Freiberg

et al. 2010

Journal of Biological Chemistry

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115

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The defense against oxidative stress is a critical feature that prevents cellular and DNA damage. UDP-glucuronosyltransferases (UGTs) catalyze the glucuronidation of xenobiotics, mutagens, and reactive metabolites and thus act as indirect antioxidants. Aim of this study was to elucidate the regulation of UGTs expressed in the mucosa of the gastrointestinal tract by xenobiotics and the main mediator of antioxidant defense, Nrf2 (nuclear factor erythroid 2-related factor 2). Xenobiotic (XRE) and antioxidant (ARE) response elements were detected in the promoters of UGT1A8, UGT1A9, and UGT1A10. Reporter gene experiments demonstrated XRE-mediated induction by dioxin in addition to tert-butylhydroquinone (ARE)-mediated induction of UGT1A8 and UGT1A10, which are expressed in extrahepatic tissue in humans in vivo. The responsible XRE and ARE motifs were identified by mutagenesis. Small interfering RNA knockdown, electrophoretic mobility shifts, and supershifts identified a functional interaction of Nrf2 and the aryl hydrocarbon receptor (AhR). Induction of UGT1A8 and UGT1A10 requires Nrf2 and AhR. It proceeds by utilizing XRE-as well as ARE-binding motifs. In summary, we demonstrate the coordinated AhR-and Nrf2-dependent transcriptional regulation of human UGT1As. Cellular protection by glucuronidation is thus inducible by xenobiotics via AhR and by oxidative metabolites via Nrf2 linking glucuronidation to cellular protection and defense against oxidative stress.

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Extrahepatic Drug‐Metabolizing Enzymes and Their Significance

Jhajra

Varkhede

Ahire

et al. 2012

Encyclopedia of Drug Metabolism and Interactions

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Drug‐metabolizing enzymes (DMEs) are primarily expressed in the liver but their role in the extrahepatic tissues such as gastrointestinal tract (GIT), pulmonary, excretory, nervous, cardiovascular system, and skin cannot be neglected. Generally, the expression of DMEs in extrahepatic tissues is quantitatively lower than that in the liver, but there are a few enzymes such as CYP1A1, CYP1B1, CYP2F1, and CYP2U1 that are more abundant in extrahepatic organs. As many extrahepatic organs are portals for administered drugs, DMEs expressed in these organs can be responsible for significant metabolism, leading to first‐pass effects and lower bioavailability. Extrahepatic DMEs are also involved in bioactivation of prodrugs and formation of reactive metabolites that may interact with cellular components, resulting in organ‐specific toxicity. Activity and expression of extrahepatic DMEs is often altered by coadministered drugs, leading to drug–drug interactions. Expression of DMEs in living beings affected by a host of environmental and genetic factors such as genetic polymorphism, age, gender, pathophysiological conditions, inborn errors in metabolism, food habits, and environmental pollutants, contributing to varied drug effects and idiosyncratic toxicities.

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Variability and Function of Family 1 Uridine-5′-Diphosphate Glucuronosyltransferases (UGT1A)

Cited by 62 publications

References 194 publications

Impact of UGT1A1 gene variants on total bilirubin levels in Gilbert syndrome patients and in healthy subjects

Impact of UGT1A1 gene variants on total bilirubin levels in Gilbert syndrome patients and in healthy subjects

Interaction between Oxidative Stress Sensor Nrf2 and Xenobiotic-activated Aryl Hydrocarbon Receptor in the Regulation of the Human Phase II Detoxifying UDP-glucuronosyltransferase 1A10

Extrahepatic Drug‐Metabolizing Enzymes and Their Significance

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