Disease relevance of UGT2B7

• Our results also have toxicogenetic significance, as UGT2B7 is polymorphic and could potentially result in genetic differences in glucuronidation of 1'-HE and, hence, toxicity of estragole [1].
• Current knowledge does not provide any ready explanation for the apparent increase in UGT2B7 expression in carcinomas in situ [2].
• Two maltose binding protein fusion proteins, 2B7F1 and 2B7F2, incorporating the first 157 or 119 amino acids, respectively, of UGT2B7 were expressed in Escherichia coli and purified by affinity chromatography [3].
• In liver microsomes from four patients (A, B, C, and D) with Crigler-Najjar syndrome type I (CN type I), UDPGT activity towards bilirubin was undetectable (A, B, C, and D) and activity towards phenolic compounds and 5-hydroxytryptamine either reduced (A and B) or normal (C and D) [4].
• Concurrent with this decrease in T4 was an increase in TSH levels, an increase in thyroid and liver weights, a three- to sixfold increase in hepatic T4-uridine diphosphate glucuronosyl transferase (UDPGT) activity, and increases in thyroid follicular cell hypertrophy and hyperplasia [5].

High impact information on UGT2B7

• These findings suggest considerable heterogeneity with regard to the expression of UDPGT isoenzymes among CN type I patients [4].
• Genetic susceptibility to diclofenac-induced hepatotoxicity: contribution of UGT2B7, CYP2C8, and ABCC2 genotypes [6].
• CONCLUSIONS: Allelic variants of UGT2B7, CYP2C8, and ABCC2, which may predispose to the formation and accumulation of reactive diclofenac metabolites are associated with diclofenac hepatotoxicity [6].
• Genotyping for several polymorphisms in the genes encoding UGT2B7, CYP2C8, and ABCC2 was performed and haplotypes assigned [6].
• Characterization of common UGT1A8, UGT1A9, and UGT2B7 variants with different capacities to inactivate mutagenic 4-hydroxylated metabolites of estradiol and estrone [7].

Chemical compound and disease context of UGT2B7

• Therefore, it is postulated that lithocholic acid toxicity may be due to down-regulation of genes involved in its detoxification, including UGT2B7, leading to limited excretion of lithocholic acid from the body [8].
• Crigler-Najjar syndrome type 1 (CN type 1) is an autosomal recessive disorder characterized by nonhemolytic jaundice resulting from mutations to the gene encoding bilirubin-UDP-glucuronosyltransferase (UDPGT) [9].

Biological context of UGT2B7

• Analysis of UGT2B4 and UGT2B7 revealed no significant stereoselectivity, but these two enzymes differed in glucuronidation kinetics [10].
• In this article, we report the genomic organization and the promoter region of the human UGT2B7 gene [11].
• The UGT2B7 gene is composed of six exons spanning approximately 16 kb, with introns ranging from 0.7 to 4.2 kb [11].
• The reported tyrosine to histidine polymorphism in UGT2B7 does not alter the formation rate of epirubicin glucuronide, and undiscovered genetic polymorphisms in UGT2B7 might change the metabolic fate of this important anticancer agent [12].
• To isolate this gene, a P-1 artificial chromosome (PAC) library was screened with a full length UGT2B7 probe and a clone of approximately 100 kb in length was isolated [11].

Anatomical context of UGT2B7

• RT-PCR experiments demonstrate the expression of UGT2B7 in human kidney and in renal proximal tubule epithelial cells, suggesting that mineralocorticoids and glucocorticoids are metabolized in their target tissue [13].
• Northern analysis of the UGT2B7 isoform in 12 placentas revealed a 10-fold difference in expression with RT-PCR variability and the 13-fold variation observed in UGT activity [14].
• These findings suggested that trans-3'-hydroxycotinine O-glucuronidation in human liver microsomes is catalyzed by mainly UGT2B7 and, to a minor extent, by UGT1A9 [15].
• The K(m) value of denopamine glucuronidation in recombinant UGT2B7 microsomes was close to those in human liver and jejunum microsomes [16].
• Caco-2 cells treated with typical enzyme-inducing agents resulted in low UGT2B7 expression but failed to mimic the UGT1A1 levels found in human small bowel [17].

Associations of UGT2B7 with chemical compounds

• PURPOSE: Ketoconazole has been shown to inhibit the glucuronidation of the UGT2B7 substrates zidovudine and lorazepam [18].
• UGT2B7 was demonstrated to glucuronidate estrogens, catechol estrogens, and androstane-3alpha,17beta-diol more efficiently than any other human UGTB isoform [19].
• Human uridine diphosphate-glucuronosyltransferase UGT2B7 conjugates mineralocorticoid and glucocorticoid metabolites [13].
• For the first time, a significant difference between the two allelic variants of UGT2B7 is described, because UGT2B7H((268)) possesses an 11-fold higher aldosterone glucuronidation efficiency (ratio Vmax((app.))/Km((app.))) than UGT2B7Y((268)) [13].
• Valproic acid inhibited UGT1A9 catalyzed propofol glucuronidation in an uncompetitive manner and UGT2B7 catalyzed AZT glucuronidation competitively (K(i)=1.6+/-0.06mM) [20].
• Both UGT2B7 polymorphisms and co-medications significantly influenced AcMPAG production, but cyclosporin and tacrolimus hindered the phenotypic impact of this trait [21].

Physical interactions of UGT2B7

• These studies indicate that UGT2B7 has one binding site and that UGT1A1 has two or more binding sites for xenobiotics and endobiotics [22].

Enzymatic interactions of UGT2B7

• The effects of P450 isozymes on the kinetic parameters of UGT2B7-catalyzed glucuronidation of the morphine 3-hydroxyl group were examined by simultaneous expression of UGT2B7 and either CYP3A4, -1A2, or -2C9 in COS-1 cells [23].
• UGT2B7 catalyzed the addition of the glucose and glucuronic acid moieties to an hydroxyl group on HDCA and also possessed some capacity to use UDP-xylose as sugar donor [24].

Regulatory relationships of UGT2B7

• Addition of CYP3A4 to untreated COS microsomes expressing UGT2B7 had no or minor effects on morphine glucuronidation [23].
• Vmax for 1A9 was fourfold higher than that measured for UGT2B7, 92 compared with 21 pmol min(-1) mg(-1), respectively, but UGT1A9 was expressed at approximately twofold higher level than the UGT2B7 in the recombinant cell lines [25].

Other interactions of UGT2B7

• UGT2B4 demonstrates reactivity toward 5alpha-reduced androgens and catechol estrogens, but at a significantly lower level than UGT2B7, 2B15, and 2B17 [19].
• These results imply that concomitant chronic intake of therapeutic drugs and dietary components that are UGT2B7 and/or UGT1A9 substrates may interfere with estragole metabolism [1].
• The activity supported by UGT2B7 and UGT2B15 was very low and restricted to cis-resveratrol [26].
• Immunoblot analysis demonstrated the presence of UGT1A6 and UGT2B7 in stomach and throughout the intestine [27].
• Kinetic analysis showed that UGT2B7 exhibits much higher glucuronidation efficiency (Vmax/Km) with ibuprofen, ketoprofen, and others, compared to UGT1A3 [28].

Analytical, diagnostic and therapeutic context of UGT2B7

• However, UGT2B7 exclusively formed SCH 488128, a trace metabolite detected in dog and human plasma samples after oral administration of ezetimibe [29].
• In order to identify more specifically the mRNAs detected in Northern blot analysis we used RNase protection and RT-PCR, although, these approaches did not allow detection of UGT2B7 transcripts [30].
• Immunoprecipitation of UGT from solubilized human liver microsomes resulted in coprecipitation of CYP3A4 with UGT2B7 [23].
• These studies suggest that UGT2B7 may play an important role in the overall contribution of morphine analgesia by serving to generate the potent morphine-6-O-glucuronide in situ [31].
• We have demonstrated the subcellular localization of the human UDP-glucuronosyltransferases (UGTs), UGT2B7 and UGT1A6, in endoplasmic reticulum (ER) and nuclear membrane from human hepatocytes and cell lines, by in situ immunostaining and Western blot [32].

References