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The aim of the present study was to investigate the allele and genotype frequencies and haplotype structures of the variants in the UGT1A1 gene and their association with serum bilirubin levels in healthy adults. Total serum bilirubin levels were measured in 300 healthy adults (normal hematology and liver function test) and genotyping of seven SNPs was performed by PCR-RFLP, Gene Scan analysis and direct sequencing on the ABI Prism 310 Genetic Analyzer. Of the seven SNPs, four were found to be polymorphic and the frequencies of minor alleles were 0.336, 0.431, 0.353 and 0.066 for − 53(TA)7, − 3279G, − 3156A and 211A respectively. Individuals who carried the − 53(TA)7, − 3279G and − 3156A mutant alleles in homozygous or heterozygous states had significantly higher mean serum bilirubin levels. Five major promoter haplotypes were observed: − 53(TA)6/− 3279T/− 3156G was the most common haplotype, followed by − 53(TA)7/− 3279G/− 3156A, − 53(TA)6/− 3279G/− 3156G, − 53(TA)6/− 3279G/− 3156A and − 53(TA)7/− 3279T/− 3156G with an estimated frequency of 0.445, 0.230, 0.083, 0.065 and 0.050 respectively. Furthermore, the mutant haplotype (− 53(TA)7/− 3279G/− 3156A) was found to have a significant effect on bilirubin concentrations. Promoter polymorphisms and a common haplotype of the UGT1A1 gene are associated with serum bilirubin concentrations and could be a genetic risk factor for hyperbilirubinemia in Indians. 相似文献
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Role of the carboxyl terminal stop transfer sequence of UGT1A6 membrane protein in ER targeting and translocation of upstream lumenal domain 总被引:1,自引:0,他引:1
We investigated the role of the stop transfer sequence of human UGT1A6 in ER assembly and enzyme activity. We found that this sequence was able to address and translocate the upstream lumenal domain into microsomal membranes in vitro co- and posttranslationally. The signal activity of this sequence was further demonstrated in HeLa cells by its ability to target and maintain the CD4 protein deleted from both the N-terminal signal peptide and C-terminal transmembrane domain into the ER. We showed that total or partial deletion of the stop transfer sequence of UGT1A6 severely impaired enzyme activity highlighting its importance in both membrane assembly and function. 相似文献
75.
Okawa H Motohashi H Kobayashi A Aburatani H Kensler TW Yamamoto M 《Biochemical and biophysical research communications》2006,339(1):79-88
Nrf2 is a key regulator of many detoxifying enzyme genes, and cytoplasmic protein Keap1 represses the Nrf2 activity under quiescent conditions. Germ line deletion of the keap1 gene results in constitutive activation of Nrf2, but the pups unexpectedly died before weaning. To investigate how constitutive activation of Nrf2 influences the detoxification system in adult mice, we generated mice bearing a hepatocyte-specific disruption of the keap1 gene. Homozygous mice were viable and their livers displayed no apparent abnormalities, but nuclear accumulation of Nrf2 is elevated. Microarray analysis revealed that, while many detoxifying enzyme genes are highly expressed, some of the typical Nrf2-dependent genes are only marginally increased in the Keap1-deficient liver. The mutant mice were significantly more resistant to toxic doses of acetaminophen than control animals. These results demonstrate that chronic activation of Nrf2 confers animals with resistance to xenobiotics without affecting the morphological and physiological integrity of hepatocytes. 相似文献
76.
During the course of the study of UGT1A1 induction by bilirubin, we could not detect the induction of the reporter gene (−3174/+14)
of human UGT1A1 in HepG2 by bilirubin (Mol. Biol. Rep. 31: 151–158 (2004)). In this report, we show the finding of the induction
of the reporter gene of UGT1A1 by cortisol at 1 μM, a major natural cortico-steroid, with human glucocorticoid receptor (GR).
RU486 of a typical GR antagonist at 10 μM inhibited the induction by cortisol from 5.9- to 1.8-fold. This result indicates
that the induction by cortisol-GR is dependence on ligand-binding. This induction is caused by the UGT reporter gene itself,
from the results of noinduction with control vector pGL2 (equal to pGV-C) in the presence of cortisol-GR. We confirmed that
the induction of the reporter gene by cortisol is dependent on the position of proximal element (−97/−53) of UGT1A1. From
this result, we concluded that the increase of corticosteroid in neonates must induce the elevation of UGT1A1 after birth
and prevent jaundice. With the study of induction by corisol, we studied the influence of co-expression of PXR (pregnenolone
xenobiotic receptor) with the UGT1A1 reporter gene and we could not find the induction of UGT1A1 expression in the presence
of dexamethasone, rifampicin, or pregnenolone 16α-carbonitrile of the PXR ligands. These results suggest that the induction
of UGT1A1 expression by GR is not mediated by PXR, unlike the induction of CYP3A4 through PXR. 相似文献
77.
Nishiyama T Fujishima M Masuda Y Izawa T Ohnuma T Ogura K Hiratsuka A 《Archives of biochemistry and biophysics》2008,478(1):75-80
Phenylbutazone (PB) is known to be biotransformed to its O- and C-glucuronide. Recently, we reported that PB C-glucuronide formation is catalyzed by UGT1A9. Interestingly, despite UGT1A8 sharing high amino acid sequence identity with UGT1A9, UGT1A8 had no PB C-glucuronidating activity. In the present study, we constructed eight UGT1A9/UGT1A8 chimeras and evaluated which region is important for PB C-glucuronide formation. All of the chimeras and UGT1A8 and UGT1A9 had 7-hydroxy-(4-trifluoromethyl)coumarin (HFC) O-glucuronidating activity. The Km values for HFC glucuronidation of UGT1A8, UGT1A9 and their chimeras were divided into two types, UGT1A8 type (high Km) and UGT1A9 type (low Km), and these types were determined according to whether their amino acids at positions 69-132 were those of UGT1A8 or UGT1A9. Likewise, PB O-glucuronidating activity was also detected by all of the chimeras, and their Km values were divided into two types. On the contrary, PB C-glucuronidating activity was detected by UGT1A9(1-132)/1A8(133-286), UGT1A9(1-212)/1A8(213-286), UGT1A8(1-68)/1A9(69-286), and UGT1A8(1-68)/1A9(69-132)/1A8(133-286) chimeras. The region 1A9(69-132) was common among chimeras having PB C-glucuronidating activity. Of interest is that UGT1A9(1-68)/1A8(69-132)/1A9(133-286) had lost PB C-glucuronidation activity, but retained activities of PB and HFC O-glucuronidation. These results strongly suggested that amino acid positions 69-132 of UGT1A9 are responsible for chemoselectivity for PB and affinity to substrates such as PB and HFC. 相似文献
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Structural organization and classification of cytochrome P450 genes in flax (Linum usitatissimum L.)
Flax CYPome analysis resulted in the identification of 334 putative cytochrome P450 (CYP450) genes in the cultivated flax genome. Classification of flax CYP450 genes based on the sequence similarity with Arabidopsis orthologs and CYP450 nomenclature, revealed 10 clans representing 44 families and 98 subfamilies. CYP80, CYP83, CYP92, CYP702, CYP705, CYP708, CYP728, CYP729, CYP733 and CYP736 families are absent in the flax genome. The subfamily members exhibited conserved sequences, length of exons and phasing of introns. Similarity search of the genomic resources of wild flax species Linum bienne with CYP450 coding sequences of the cultivated flax, revealed the presence of 127 CYP450 gene orthologs, indicating amplification of novel CYP450 genes in the cultivated flax. Seven families CYP73, 74, 75, 76, 77, 84 and 709, coding for enzymes associated with phenylpropanoid/fatty acid metabolism, showed extensive gene amplification in the flax. About 59% of the flax CYP450 genes were present in the EST libraries. 相似文献
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Michaela Gruber Trang Le Martin Filipits Andrea Gsur Christine Mannhalter Ulrich Jäger Katrina Vanura 《Cancer epidemiology》2013,37(5):625-628
Background: The enzyme uridine diphospho glucuronosyltansferase 2B17 (UGT2B17) glucuronidates several endogenous and exogenous compounds, including carcinogens from tobacco smoke like 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanl (NNAL). UGT2B17 shows a remarkable copy number variation (CNV) and an association between deletion genotype and increased risk of lung adenocarcinoma in women has been previously reported. Methods: We investigated the UGT2B17 CNV by PCR in 453 Austrian lung cancer patients and in 449 healthy donors and analyzed the impact on lung cancer susceptibility and outcome. Results: Copy numbers of UGT2B17 were 44.4% (+/+), 42.2% (+/?) and 13.5% (?/?) in lung cancer patients and 43.0% (+/+), 46.3% (+/?) and 10.7% (?/?) among healthy donors. The null genotype was not significantly more frequent among women with adenocarcinoma compared to healthy women (p = 0.59). There was no association with overall survival (p = 0.622) and no significant sex-associated (p = 0.423) or histology-related impact on development of lung cancer. Conclusion: UGT2B17 deletion genotype was not associated with a significant risk for lung cancer development or outcome in our Central European patient cohort. Our study indicates that UGT2B17 is not a crucial factor in lung carcinogenesis among Caucasians and shows the importance of investigating such markers in large cohorts from different populations. 相似文献
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Paulina Sosicka Piotr Jakimowicz Teresa Olczak Mariusz Olczak 《Biochemical and biophysical research communications》2014
UDP-galactose transporter (UGT) and UDP-N-acetylglucosamine transporter (NGT) form heterologous complexes in the Golgi apparatus (GA) membrane. We aimed to identify UGT region responsible for galactosylation of N-glycans. Chimeric proteins composed of human UGT and either NGT or CMP-sialic acid transporter (CST) localized to the GA, and all but UGT/CST chimera corrected galactosylation defect in UGT-deficient cell lines, although at different efficiency. Importantly, short N-terminal region composed of 35 N-terminal amino-acid residues of UGT was crucial for galactosylation of N-glycans. The remaining molecule must be derived from NGT not CST, confirming that the role played by UGT and NGT is coupled. 相似文献