HUMANGGP:011459 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: HUMANGGP:011459 (UGT2B11)
19 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The capacity of four cDNA-expressed human liver UDP-glucuronosyltransferases (UGT), UGT1*6, UGT2B7, UGT2B10 and UGT2B11, to glucuronidate hydroxylated metabolites of benzo[a]pyrene (B[a]P) and 2-acetylaminofluorene (AAF) has been investigated. UGT1*6 and UGT2B7 glucuronidated a range of B[a]P and AAF metabolites with a degree of regiospecificity, although UGTs 2B10 and 2B11 were inactive towards all compounds screened. UGT2B7 glucuronidated the B[a]P trans 4,5- and 7,8-dihydrodiols and the 1-,2-,4-,5-,6-,8-,9- and 10-monophenols. In contrast, UGT1*6 lacked activity towards the dihydrodiols and metabolized a more limited range of monophenols, namely 4-,5-,8- and 12-hydroxyB[a]P. Both UGT2B7 and UGT1*6 glucuronidated N, 1-,3- and 8-hydroxyAAF, but 5-hydroxyAAF was metabolised only by UGT1*6. Neither enzyme glucuronidated 3-,7- and 11-hydroxyB[a]P and 7- and 9-hydroxyAAF, although these compounds were all metabolised by human liver microsomal UGTs. The results suggest that the relative content of UGT isoforms in a cell or tissue will be important for determining the extent to which a particular carcinogen/mutagen is deactivated.
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PMID:The glucuronidation of hydroxylated metabolites of benzo[a]pyrene and 2-acetylaminofluorene by cDNA-expressed human UDP-glucuronosyltransferases. 826 38

Two new UDP-glucuronosyltransferase cDNAs, designated UGT2B10 and UGT2B11, encoding 528 amino acid proteins were isolated from a human liver cDNA library. The deduced amino acid sequences of UGTs 2B10 and 2B11 share > 76% sequence similarity with other known human liver UGT2B subfamily isoforms and < 48% sequence similarity with UGT1 family proteins. COS-7 cells transfected with UGT 2B10 and 2B11 synthesized proteins with respective molecular masses of 49kDa and 51kDa. UGT2B11 expressed in COS-7 cells glucuronidated a number of polyhydroxylated estrogens (estriol, 4-hydroxyestrone and 2-hydroxyestriol) and xenobiotics (4-methylumbelliferone, 1-naphthol, 4-nitrophenol, 2-aminophenol, 4-hydroxybiphenyl and menthol). Despite the screening of more than forty potential substrates, glucuronidation activity was not observed for expressed UGT2B10.
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PMID:cDNA cloning and expression of two new members of the human liver UDP-glucuronosyltransferase 2B subfamily. 833 63

The capacity of two human hepatic UDP-glucuronosyltransferase (UGT) isoforms, UGT2B7 and UGT2B11, to metabolize more than 50 hydroxylated androgens and pregnanes was investigated. All mono- and dihydroxylated androgens with a hydroxyl function in the 3 alpha, 6 alpha, and 17 beta positions were glucuronidated by UGT2B7, but highest activity was generally observed for steroids containing a 3 alpha-hydroxy substituent. UGT2B7 did not glucuronidate 2 alpha-, 2 beta-, 3 beta-, 6 beta-, 7 alpha-, 11 alpha-, and 11 beta-monohydroxylated androgens, although the presence of hydroxyl groups at certain of these positions did not abolish the ability of UGT2B7 to metabolize diols which also possessed a 3 alpha- or 17 beta-hydroxyl group. 3 alpha-Hydroxypregnanes were also glucuronidated by UGT2B7. Activity was not detected for 6 alpha-, 6 beta-, 11 beta-, 12 alpha-, 16 alpha-, 17 alpha-, 20 alpha-, or 21-monohydroxylated pregnanes. Although 11 alpha-hydroxylated androgens were not glucuronidated by UGT2B7, this enzyme exhibited high activity toward the 11 alpha-hydroxylated derivatives of 5 beta-prenanedione and progesterone. UGT2B11 similarly glucuronidated 3 alpha-hydroxyandrogens and -pregnanes, but rates of metabolism were low compared to UGT2B7. With the exception of androsterone and its 5 beta-isomer, ring A/B stereochemistry appeared not to influence rates of hydroxysteroid glucuronidation by UGT2B7 and UGT2B11. Overall, the data indicate a high degree of stereo- and regioselectivity in the glucuronidation of hydroxyandrogens and -pregnanes by UGT2B7 and UGT2B11 and further suggest that UGT2B7 may contribute to the glucuronidation of 3 alpha-hydroxysteroids in humans.
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PMID:The regio- and stereo-selectivity of C19 and C21 hydroxysteroid glucuronidation by UGT2B7 and UGT2B11. 916 6

Glucuronidation is an important metabolic pathway for both endogenous and exogenous compounds. To isolate novel UGT2B cDNA clones, human prostate and LNCaP cell cDNA libraries were screened using a pool of steroid-specific UGT2B cDNA as probes. We have isolated a novel human cDNA of 1.7 kb in length containing an open reading frame of 1587 pb which encodes a deduced protein of 529 residues named UGT2B11. UGT2B11 share 91% identity in amino acids with UGT2B10, a UDP-glucuronosyltransferase (UGT) protein with unknown function. In agreement with other characterized UGT2B proteins, a Western blot analysis showed high levels of a 52-kDa protein present in a microsome preparation from HK293 cells stably transfected with the UGT2B11 cDNA. Despite the screening of 100 potential substrates, glucuronidation activity was not detected for the stably expressed UGT2B11 protein. However, UGT2B11 specific RT-PCR analysis revealed expression of the transcripts in a wide range of human tissues including the liver, kidney, mammary gland, prostate, skin, adipose, adrenal, and lung. The biological function of the UGT2B11 protein is unknown but its wide expression in human tissues raises the possibility that UGT2B11 may constitute an orphan UGT enzyme whose substrates specificity remain to be identified.
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PMID:Isolation and characterization of a human orphan UDP-glucuronosyltransferase, UGT2B11. 967 83

Variations in glucuronidation activities among different individuals have been reported; however, genetic polymorphisms in the genes encoding phase II drug metabolizing UDP-glucuronosyltransferases have not been studied extensively. A novel UGT2B cDNA clone UGT2B4(E458) was isolated from human prostate and LNCaP cell cDNA libraries. The cDNA encoding UGT2B4(E458) is 2097 bp in length and has an open reading frame of 1584 nucleotides encoding a protein of 528 amino acids. Characterization of the UGT2B4(E458) cDNA revealed nucleotide differences with the previously published UGT2B4 and UGT2B11 cDNAs. These variations in the UGT2B4 sequence lead to an amino acid change from aspartic acid to glutamic acid at position 458. In the previous UGT2B11 cDNA (which has subsequently been renamed UGT2B4 (L109,396, D458)), leucine residues are found at positions 109 and 396, whereas phenylalanines are present at these positions in the UGT2B4(D458) and UGT2B4(E458) enzymes. Analysing the genomic DNA of 26 unrelated Caucasian individuals demonstrated the presence of variant alleles encoding UGT2B4(D458) and UGT2B4(E458). Stable expression of UGT2B4(E458) cDNA in HK293 cells demonstrates the presence of a 52 kDa protein, which is in agreement with other characterized (UGT2B proteins. UGT2B4(E458) conjugates hyodeoxycholic acid (HDCA) as well as 4-hydroxyestrone (4-OH-E1), androstane-3alpha,17beta-diol (3alpha-diol) and androsterone (ADT). Specific reverse transcriptase-polymerase chain reaction analysis revealed expression of UGT2B4(D458) and UGT2B4(E458) transcripts in a wide range of extrahepatic tissues, including the liver, kidney, testis, mammary gland, prostate, placenta, adipose, adrenal, skin and lung. Our results suggest that UGT2B4(E458) and UGT2B(E458) are two widely expressed isoenzymes, and that polymorphism in the UGT2B4 gene might be responsible for differences in UGT2B4 enzymatic properties.
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PMID:Characterization and substrate specificity of UGT2B4 (E458): a UDP-glucuronosyltransferase encoded by a polymorphic gene. 1037 68

Glucuronidation is a major pathway of androgen metabolism and is catalyzed by UDP-glucuronosyltransferase (UGT) enzymes. UGT2B15 and UGT2B17 are 95% identical in primary structure, and are expressed in steroid target tissues where they conjugate C19 steroids. Despite the similarities, their regulation of expression are different; however, the promoter region and genomic structure of only the UGT2B17 gene have been characterizedX to date. To isolate the UGT2B15 gene and other novel steroid-conjugating UGT2B genes, eight P-1-derived artificial chromosomes (PAC) clones varying in length from 30 kb to 165 kb were isolated. The entire UGT2B15 gene was isolated and characterized from the PAC clone 21598 of 165 kb. The UGT2B15 and UGT2B17 genes are highly conserved, are both composed of six exons spanning approximately 25 kb, have identical exon sizes and have identical exon-intron boundaries. The homology between the two genes extend into the 5'-flanking region, and contain several conserved putative cis-acting elements including Pbx-1, C/EBP, AP-1, Oct-1 and NF/kappaB. However, transfection studies revealed differences in basal promoter activity between the two genes, which correspond to regions containing non-conserved potential elements. The high degree of homology in the 5'-flanking region between the two genes is lost upstream of -1662 in UGT2B15, and suggests a site of genetic recombination involved in duplication of UGT2B genes. Fluorescence in situ hybridization mapped the UGT2B15 gene to chromosome 4q13.3-21.1. The other PAC clones isolated contain exons from the UGT2B4, UGT2B11 and UGT2B17 genes. Five novel exons, which are highly homologous to the exon 1 of known UGT2B genes, were also identified; however, these exons contain premature stop codons and represent the first recognized pseudogenes of the UGT2B family. The localization of highly homologous UGT2B genes and pseudogenes as a cluster on chromosome 4q13 reveals the complex nature of this gene locus, and other novel homologous UGT2B genes encoding steroid conjugating enzymes are likely to be found in this region of the genome.
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PMID:Isolation and characterization of the human UGT2B15 gene, localized within a cluster of UGT2B genes and pseudogenes on chromosome 4. 1062 41

Androgens and estrogens play major roles in cell differentiation, cell growth, and peptide secretion in steroid target tissues. In addition to the binding of these hormones to their receptors, formation and metabolism are important in the action of steroids. Metabolism of the potent steroid hormones includes glucuronidation, a major pathway of steroid elimination in liver and several steroid target tissues. Glucuronidation is catalyzed by UDP-glucuronosyltransferases (UGTs), which transfer the polar moiety from UDP-glucuronic acid to a wide variety of endogenous compounds, including steroid hormones. The UGT superfamily of enzymes is subdivided into two families, UGT1 and UGT2, on the basis of sequence homology. To date, six UGT2B proteins have been isolated, namely UGT2B4, UGT2B7, UGT2B10, UGT2B11, UGT2B15, and UGT2B17, all of which have been demonstrated to be active on steroid molecules, except for UGT2B10 and UGT2B11, for which no substrate was found. The relative activity of these enzymes on steroidal compounds remains unknown due to variable levels of UGT2B expression in different in vitro cell line models and various conditions of the enzymatic assays. Comparison of the glucuronidation rates of these enzymes requires a unique system for UGT2B protein expression, protein normalization, and enzymatic assays. In this study we have stably expressed UGT2B4, UGT2B7, UGT2B15, and UGT2B17 in the HK293 cell line, which is devoid of steroid UGT activity; characterized their kinetic properties relative to UGT protein expression; determined their transcript and protein stabilities; and established extensively their tissular distributions. UGT2B7 was demonstrated to glucuronidate estrogens, catechol estrogens, and androstane-3alpha,17beta-diol more efficiently than any other human UGTB isoform. UGT2B15 and UGT2B17 showed similar glucuronidation activity for androstane-3alpha,17beta-diol (30% lower than that of UGT2B7), whereas UGT2B17 demonstrated the highest activity for androsterone, testosterone, and dihydrotestosterone. UGT2B4 demonstrates reactivity toward 5alpha-reduced androgens and catechol estrogens, but at a significantly lower level than UGT2B7, 2B15, and 2B17. Cycloheximide treatment of stably transfected HK293 cells demonstrated that the UGT2B17 protein is more labile than the other enzymes; the protein levels decrease after 1 h of treatment, whereas other UGT2B proteins were stable for at least 12 h. Treatment of stable cells with actinomycin D reveals that UGT2B transcripts are stable for 12 h, except for the UGT2B4 transcript, which was decreased by 50% after the 12-h incubation period. Tissue distribution of the UGT2B enzymes demonstrated that UGT2B isoforms are expressed in the liver as well as in several extrahepatic steroid target tissues, namely, kidney, breast, lung, and prostate. This study clearly demonstrates the relative activities and the major substrates of human steroid-metabolizing UGT2B enzymes, which are expressed in a wide variety of steroid target tissues.
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PMID:Relative enzymatic activity, protein stability, and tissue distribution of human steroid-metabolizing UGT2B subfamily members. 1115 50

Arachidonic acids (AA) and linoleic acids (LAs) are metabolized, in several tissues, to hydroxylated metabolites that are important mediators of many physiological and pathophysiological processes. The conjugation of leukotriene B4 (LTB4), 5-hydroxyeicosatetraenoic acid (HETE), 12-HETE, 15-HETE, and 13-hydroxyoctadecadienoic acid (HODE) by the human UDP-glucuronosyltransferase (UGT) enzymes was investigated. All substrates tested were efficiently conjugated by human liver microsomes to polar derivatives containing the glucuronyl moiety as assessed by mass spectrometry. The screening analyses with stably expressed UGT enzymes in HK293 showed that glucuronidation of LTB4 was observed with UGT1A1, UGT1A3, UGT1A8, and UGT2B7, whereas UGT1A1, UGT1A3, UGT1A4, and UGT1A9 also conjugated most of the HETEs and 13-HODE. LA and AA metabolites also appear to be good substrates for the UGT2B subfamily members, especially for UGT2B4 and UGT2B7 that conjugate all HETE and 13-HODE. Interestingly, UGT2B10 and UGT2B11, which are considered as orphan enzymes since no conjugation activity has so far been demonstrated with these enzymes, conjugated 12-HETE, 15-HETE, and 13-HODE. In summary, our data showed that several members of UGT1A and UGT2B families are capable of converting LA and AA metabolites into glucuronide derivatives, which is considered an irreversible step to inactivation and elimination of endogenous substances from the body.
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PMID:Glucuronidation of arachidonic and linoleic acid metabolites by human UDP-glucuronosyltransferases. 1263 71

Androgens as well as monohydroxy-fatty acids are implicated in the pathogenesis of prostate cancer. Like a huge variety of endo- and xenobiotics, they are eliminated as glucuronide conjugates formed by uridine diphosphate-glucuronosyltransferase (UGT) enzymes. In the present study, we observe that treatment of the prostate cancer cells LNCaP with natural and synthetic androgens, IL-1alpha, or epidermal growth factor (EGF) differently modulates the glucuronidation of androgen and bioactive lipid metabolites. Indeed, glucuronidation of 5alpha-androstane-3alpha,17beta-diol and 13-hydroxyoctadecadienoic acid was drastically reduced, whereas 12-hydroxyeicosatetraenoic acid conjugation by UGT was increased after androgen treatment. These effects reflected the reduction of UGT2B10, -B15, and -B17 enzyme expression, and the activation of the UGT2B11 gene. In human prostate epithelial cells, only UGT2B11 and -B15 mRNAs are detected and are regulated by androgens in a similar manner as in LNCaP cells. In LNCaP cells, IL-1alpha and EGF also regulate UGT2B expression in an isoform-specific manner; IL-1alpha induced UGT2B10 and reduced UGT2B17, while having no effects on UGT2B11 mRNA levels. EGF treatment resulted in a decreased UGT2B17 expression, whereas UGT2B10 and -B11 mRNA remained at their basal levels. Overall, these results demonstrate that in the human prostate, androgens do not only affect their own inactivation but also influence the levels of monohydroxy-fatty acids by regulating the expression of UGT2B enzymes in an isoform-specific manner. These differential effects of androgens, IL-1alpha, and EGF on lipid metabolism likely constitute an additional mechanism by which these endogenous factors promote prostate cancer development.
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PMID:Isoform-specific regulation of uridine diphosphate-glucuronosyltransferase 2B enzymes in the human prostate: differential consequences for androgen and bioactive lipid inactivation. 1688 6

Intrahepatic cholangiocarcinoma (ICC) is the second most common primary cancer in the liver, and its incidence is highest in the northeastern part of Thailand. ICCs in this region are known to be associated with infection with liver flukes, particularly Opisthorchis viverrini (OV), as well as nitrosamines from food. To clarify molecular mechanisms of ICC associated with or without liver flukes, we analyzed gene expression profiles of OV-associated ICCs from 20 Thai patients and compared their profiles with those of 20 Japanese ICCs that were not associated with OV, by means of laser microbeam microdissection and a cDNA microarray containing 27,648 genes. We identified 77 commonly upregulated genes and 325 commonly downregulated genes in the two ICC groups. Unsupervised hierarchical cluster analysis separated the 40 ICCs into two major branches almost completely according to the fluke status. The putative signature of OV-associated ICC exhibited elevated expression of genes involved in xenobiotic metabolism (UGT2B11, UGT1A10, CHST4, SULT1C1), whereas that of non-OV-associated ICC represented enhanced expression of genes related to growth factor signaling (TGFBI, PGF, IGFBP1, IGFBP3). Additional random permutation tests identified a total of 49 genes whose expression levels were significantly different between the two groups. We also identified genes associated with macroscopic type of ICCs. In conclusion, these data may not only contribute to clarification of common and OV-specific mechanisms underlying ICC, but also may serve as a starting point for the identification of novel diagnostic markers or therapeutic targets for the disease.
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PMID:Comparison of gene expression profiles between Opisthorchis viverrini and non-Opisthorchis viverrini associated human intrahepatic cholangiocarcinoma. 1700 47

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