cDNA Cloning and Expression of Two New Members of the Human Liver UDP-Glucuronosyltransferase 2B Subfamily

Chen, Jin; Miners, John O.; Lillywhite, K. J.; Mackenzie, Peter I.

doi:10.1006/bbrc.1993.1847

Cited by 102 publications

(56 citation statements)

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“…98,144,148,155,[163][164][165][166][167][168][169] UGT2B4 is expressed in the liver and in a wide range of extrahepatic Pharmacogenomics of human UGT enzymes C Guillemette tissues. 98,144 One common polymorphism has been found in the UGT2B4 gene and the resulting variant allele is designated as UGT2B4 Asp 458 Glu (UGT2B4*2).…”

Section: Ugt2b4mentioning

confidence: 99%

“…This assumption is based on in vitro data, which suggest no functional impact of the variation at position 458 on gene product function when assessed with bile acids, phenol derivatives and catecholestrogens as substrates. 98 An additional cDNA clone isolated from human liver corresponds to the UGT2B4 Phe 109 Leu, Phe 396 Leu allele 165 and appears to be very rare as it was not found in 272 individuals that were genotyped in two independent studies. 98,149 isoforms has yet to be elucidated.…”

Section: Ugt2b4mentioning

confidence: 99%

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Pharmacogenomics of human UDP-glucuronosyltransferase enzymes

2003

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UDP-glucuronosyltransferase (UGT) enzymes comprise a superfamily of key proteins that catalyze the glucuronidation reaction on a wide range of structurally diverse endogenous and exogenous chemicals. Glucuronidation is one of the major phase II drug-metabolizing reactions that contributes to drug biotransformation. This biochemical process is also involved in the protection against environmental toxicants, carcinogens, dietary toxins and participates in the homeostasis of numerous endogenous molecules, including bilirubin, steroid hormones and biliary acids. Over the years, significant progress was made in the field of glucuronidation, especially with regard to the identification of human UGTs, study of their tissue distribution and substrate specificities. More recently, the degree of allelic diversity has also been revealed for several human UGT genes. Some polymorphic UGTs have demonstrated a significant pharmacological impact in addition to being relevant to drug-induced adverse reactions and cancer susceptibility. This review focuses on human UGTs, the description of the nature of polymorphic variations and their functional impact. The pharmacogenomic implication of polymorphic UGTs is presented, more specifically the role of UGT polymorphisms in modifying cancer risk and their impact on individual risk to drug-induced toxicities.

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Section: Ugt2b4mentioning

confidence: 99%

Section: Ugt2b4mentioning

confidence: 99%

Pharmacogenomics of human UDP-glucuronosyltransferase enzymes

2003

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“…The UGT2 genes are encoded as individual structural genes on chromosome 4 [5]. From human liver, four UGT2 cDNAs have been cloned and characterized : UGT2B4 [6], UGT2B7 [7], UGT2B10 [8] and UGT2B15 [9,10]. In contrast, the human UGT1 genes are encoded by a single locus on chromosome 2.…”

Section: Introductionmentioning

confidence: 99%

“…Some of these UGTs have unique catalytic activities catalysed by the bilirubin UGT1A1 [22], tertiary amine UGT1A4 [23] and oestrone UGT1A3 and UGT1A10 [13,18]. Conversely, recombinant UGT2B proteins exhibit a preference for endobiotic substrates, including hydroxylated steroids and bile acids [4,[6][7][8][9]. Individual isoforms such as UGT2B7 and UGT2B15 also demonstrate catalytic activity towards some xenobiotic substrates [10,24].…”

Section: Introductionmentioning

confidence: 99%

Regulation and function of family 1 and family 2 UDP-glucuronosyltransferase genes (UGT1A, UGT2B) in human oesophagus

Strassburg

Nguyen

et al. 1999

Biochemical Journal

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Human UDP-glucuronosyltransferases (UGTs) are expressed in a tissue-specific fashion in hepatic and extrahepatic tissues [Strassburg, Manns and Tukey (1998) J. Biol. Chem. 273, 8719–8726]. Previous work suggests that these enzymes play a protective role in chemical carcinogenesis [Strassburg, Manns and Tukey (1997) Cancer Res. 57, 2979–2985]. In this study, UGT1 and UGT2 gene expression was investigated in human oesophageal epithelium and squamous-cell carcinoma in addition to the characterization of individual UGT isoforms using recombinant protein. UGT mRNA expression was characterized by duplex reverse transcriptase-PCR analysis and revealed the expression of UGT1A7, UGT1A8, UGT1A9 and UGT1A10 mRNAs. UGT1A1, UGT1A3, UGT1A4, UGT1A5 and UGT1A6 transcripts were not detected. UGT2 expression included UGT2B7, UGT2B10 and UGT2B15, but UGT2B4 mRNA was absent. UGT2 mRNA was present at significantly lower levels than UGT1 transcripts. This observation was in agreement with the analysis of catalytic activities in oesophageal microsomal protein, which was characterized by high glucuronidation rates for phenolic xenobiotics, all of which are classical UGT1 substrates. Whereas UGT1A9 was not regulated, differential regulation of UGT1A7 and UGT1A10 mRNA was observed between normal oesophageal epithelium and squamous-cell carcinoma. Expression and analysis in vitro of recombinant UGT1A7, UGT1A9, UGT1A10, UGT2B7 and UGT2B15 demonstrated that UGT1A7, UGT1A9 and UGT1A10 catalysed the glucuronidation of 7-hydroxybenzo(α)pyrene, as well as other environmental carcinogens, such as 2-hydroxyamino-1-methyl-6-phenylimidazo-(4,5-β)-pyridine. Although UGT1A9 was not regulated in the carcinoma tissue, the five-fold reduction in 7-hydroxybenzo(α)pyrene glucuronidation could be attributed to regulation of UGT1A7 and UGT1A10. These data elucidate an individual regulation of human UGT1A and UGT2B genes in human oesophagus and provide evidence for specific catalytic activities of individual human UGT isoforms towards environmental carcinogens that have been implicated in cellular carcinogenesis.

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“…Transcripts have been identified for UGT2B4 (18), UGT2B7 (19), UGT2B10 (20), UGT2B11 (21), UGT2B15 (22), UGT2B17 (23,24), and UGT2A1 (17). Except for UGT2B17 and UGT2A1, hepatic expression was detected for all UGT2B transcripts.…”

mentioning

confidence: 99%

Polymorphic Gene Regulation and Interindividual Variation of UDP-glucuronosyltransferase Activity in Human Small Intestine

Strassburg¹,

Kneip²,

Topp³

et al. 2000

Journal of Biological Chemistry

226

154

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UDP-glucuronosyltransferases (UGTs) convert dietary constituents, drugs, and environmental mutagens to inactive hydrophilic glucuronides. Recent studies have shown that the expression of the UGT1 and UGT2 gene families is regulated in a tissue-specific fashion. Human small intestine represents a major site of resorption of dietary constituents and orally administered drugs and plays an important role in extrahepatic UGT directed metabolism. Expression of 13 UGT1A and UGT2B genes coupled with functional and catalytic analyses were studied using 18 small intestinal and 16 hepatic human tissue samples. Hepatic expression of UGT gene transcripts was without interindividual variation. In contrast, a polymorphic expression pattern of all the UGT genes was demonstrated in duodenal, jejunal, and ileal mucosa, with the exception of UGT1A10. To complement these studies, interindividual expression of UGT proteins and catalytic activities were also demonstrated. Hyodeoxycholic acid glucuronidation, catalyzed primarily by UGT2B4 and UGT2B7, showed a 7-fold interindividual variation in small intestinal duodenal samples, in contrast to limited variation in the presence of 4-methylumbelliferone, a substrate glucuronidated by most UGT1A and UGT2B gene products. Linkage of RNA expression patterns to protein abundance were also made with several mono-specific antibodies to the UGTs. These results are in contrast to a total absence of polymorphic variation in gene expression, protein abundance, and catalytic activity in liver. In addition, the small intestine exhibits considerable catalytic activity toward most of the different classes of substrates accepted for glucuronidation by the UGTs, which is supported by immunofluorescence analysis of UGT1A protein in the mucosal cell layer of the small intestine. Thus, tissue-specific and interindividual polymorphic regulation of UGT1A and UGT2B genes in small intestine is identified and implicated as molecular biological determinant contributing to interindividual prehepatic drug and xenobiotic metabolism in humans.

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cDNA Cloning and Expression of Two New Members of the Human Liver UDP-Glucuronosyltransferase 2B Subfamily

Cited by 102 publications

References 0 publications

Pharmacogenomics of human UDP-glucuronosyltransferase enzymes

Pharmacogenomics of human UDP-glucuronosyltransferase enzymes

Regulation and function of family 1 and family 2 UDP-glucuronosyltransferase genes (UGT1A, UGT2B) in human oesophagus

Polymorphic Gene Regulation and Interindividual Variation of UDP-glucuronosyltransferase Activity in Human Small Intestine

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