Disease relevance of UGT1A@

• The gene expression levels of UGT isoforms were examined in lung cancer cell lines and 14 lung cancer samples by semi, quantitative RT-PCR [1].
• We hypothesized that germline polymorphisms within genes related to drug target (thymidylate synthase) or metabolizing enzymes (UDP-glucuronosyltransferase, UGT) would impact response and toxicity to the combination of capecitabine plus irinotecan (CPT-11) [2].
• A total of 115 male adults with unconjugated hyperbilirubinemia were divided into six subgroups according to their glucose-6-phosphate dehydrogenase (G6PD) status (normal and deficient) and UDP-glucuronosyl transferase 1 (UGT1) A1 genotypes (heterozygous variation, compound heterozygous variation and homozygous variation) [3].
• Treatment of humans or hepatoma cell lines with drugs such as phenobarbital causes the induction of hepatic bilirubin UGT by increased transcription from the UGT1 gene [4].
• The most severe syndrome, termed Crigler-Najjar syndrome type I, is mainly associated with mutations in exons 2 to 5 that affect all UGT1 enzymes and many of the mutations result in termination codons and frameshifts [5].

High impact information on UGT1A@

• Transgenic mice expressing a constitutively active form of human PXR show markedly increased UGT activity toward steroid, heme, and carcinogens, enhanced bilirubin clearance, as well as massively increased steroid clearance [6].
• Conclusion: Our results indicate that this newly discovered alternative splicing mechanism at the UGT1A locus amplifies the structural diversity of human UGT proteins and describes the identification of an additional posttranscriptional regulatory mechanism of the glucuronidation pathway [7].
• Gene expression profiles confirmed that all of the UGT1A genes can be targeted for regulation by the pregnane X receptor activator pregnenolone-16alpha-carbonitrile (PCN) or the Ah receptor ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) [8].
• In Tg-UGT1 mice, the UGT1A proteins are differentially expressed in the liver and gastrointestinal tract [8].
• In addition, the selective induction of glucuronidation activity toward lamotrigine, ethinyl estradiol, chenodeoxycholic acid, and lithocholic acid by either PCN or TCDD in small intestine from Tg-UGT1 mice corresponded to expression of the locus in this tissue [8].

Chemical compound and disease context of UGT1A@

• Serious adverse events associated with chloramphenicol toxicity in the neonate have highlighted the importance of developmental changes in UGT activity [9].
• The gene arrangement, in conjunction with the toxicity data from the Gunn rat, leads to the prediction that detoxification of bilirubin, xenobiotics, and therapeutic drugs is linked to the UGT1 locus [10].

Biological context of UGT1A@

• BACKGROUND: We previously reported that upregulation of glucuronidation activity catalyzed by uridine 5'diphosphoglucuronosyltransferase (UGT) is one of the mechanisms associated with irinotecan hydrochloride/7-ethyl-10-hydroaxycamptothecin (CPT-11/SN-38) resistance [1].
• Only three major haplotypes were found, including a haplotype consisting of allelic variants of all three isoforms (29% in Caucasians and 22% in Egyptians), all leading to reduced UGT activity [11].
• The UGT1 gene subfamily consists of a number of UGTs that result from alternate splicing of multiple first exons and share common exons 2-5 [12].
• Genetic polymorphisms have been identified for almost all the UGT family members [13].
• Several human hepatic and extrahepatic UGT isozymes have been characterized with respect to their substrate specificity, tissue expression and gene structure [13].

Anatomical context of UGT1A@

• Glucuronidation of trans-resveratrol by human liver and intestinal microsomes and UGT isoforms [14].
• Immunochemical identification of UGT isoforms in human small bowel and in caco-2 cell monolayers [15].
• In cancer tissue, CYP1A activity was decreased in comparison with surrounding healthy mucosa (1.2 +/- 0.9 in tumor tissue vs. 2.2 +/- 0.7 pmol x min[-1] x mg protein[-1], respectively), whereas means and medians of UGT activity were unchanged [16].
• Michaelis-Menten parameters were determined for entacapone and tolcapone using recombinant human UGT isoforms and human liver microsomes to compare the kinetic properties of the two COMT inhibitors [17].
• SDS-PAGE and Western blot analysis of UGT1.1-transfected HK293 membrane proteins photolabeled with [11,12-3H]atRA revealed a protein of approximately 56 kDa that was labeled by [3H]atRA, detected by anti-pNP UGT antibody and not present in membranes from nontransfected HK293 cells [18].

Associations of UGT1A@ with chemical compounds

• Regulation of the UGT1A1 bilirubin-conjugating pathway: Role of a new splicing event at the UGT1A locus [7].
• Here we report that the two corresponding bilirubin transferases and the phenol transferase are encoded by a novel locus, UGT1, which is also predicted to encode three other bilirubin transferase-like isozymes all having identical carboxyl termini [19].
• Recessively inherited mutant alleles for the predominant bilirubin isozyme, the HUG-Br1 protein, substituted Arg for Gly at codon 276 (G276R) in exon 1 of UGT1A abolishing a conserved di-glycine [20].
• Treatment of the resulting cell lines with lipoprotein-deficient serum in the absence and presence of compactin for 5 days resulted in a 1.3- and 2.3-fold, respectively, increase of the UGT enzyme activity towards 4-methylumbelliferone, paralleled by an induction of immunoreactive UGT1A6 protein [21].
• PURPOSE: We wanted to assess polymorphisms in the uridine diphosphoglucuronosyl transferase 1A1 (UGT 1A1) gene: the TATA box polymorphism and UGT 1A1 G71R and Y486D mutations in the coding sequence, the main mutations characterizing Gilbert's syndrome, as predictors of severe toxic event occurrence after irinotecan (CPT-11) administration [22].

Enzymatic interactions of UGT1A@

• Valproate significantly inhibited UGT2B15 catalyzed steroid and xenobiotic glucuronidation although valproate was not a substrate for this UGT isoform [23].

Other interactions of UGT1A@

• In contrast, all UGT isoforms, except for UGT1A3 and UGT1A4, catalyzed O-glucuronidation of 4-HO-TAM [24].
• Two-hybrid analysis in yeast and mammalian systems demonstrated positive interaction of hUGT1A1 with itself, but not with another UGT isoform, human UGT1A6, which differs only in the N-terminal domain [25].
• UGT2B7 is the only UGT isoform for which ontogeny has been characterised both in vitro and in vivo, using morphine as the probe drug [9].
• Among six human UGT isozymes tested, UGT1A1 and 1A3 were capable of catalyzing the glucuronidation of both GFZ and SVA [26].
• AIM: To investigate the relationship between single nucleotide polymorphisms in the uridine-diphosphoglucuronosyltransferase (UGT) UGT1A7 and UGT1A1 genes and patients suffering from colorectal cancer (CRC) [27].

Analytical, diagnostic and therapeutic context of UGT1A@

• To confirm the presence of UGT1A1 isoform in human small bowel, to explore the possible absence of UGT1A6 and 2B7 in the organ, and to examine induced Caco-2 cells as a potential model for human intestinal metabolism, Western blot analysis was performed using specific antibodies to the relevant UGT isoforms [15].
• The study was carried out by immunohistochemistry, using an antiserum recognizing all the UGT1A isoforms [28].
• In summary, this review focuses on the role of the human UGT genetic polymorphisms in carcinogenesis, chemoprevention and cancer risk [13].
• Sequence analysis of both UGT1A exon 1 and common exons 2-5 was performed in all patients, leading to the detection of AF170 and a novel mutation (470insT), both residing in UGT1A exon 1 [29].
• Genetic defects at the UGT1 locus associated with Crigler-Najjar type I disease, including a prenatal diagnosis [30].

References