Disease relevance of UGT1A5

• This study reports the molecular characterisation of the bilirubin UDP-glucuronosyl-transferase gene (UGT1) in a group of patients of Sardinian descent with Crigler-Najjar syndrome type I and their relatives [1].
• In human, rat, and mice, a UGT1 complex locus provides for developmental-, inducer-, and cell-specific synthesis of a family of chemical-detoxifying isozymes, UDP-glucuronosyltransferases, which prevent toxicities, mutagenesis, and/or carcinogenesis [2].
• BACKGROUND & AIMS: Approximately 13% of patients with chronic hepatitis D virus (HDV) infection have liver-kidney microsomal antibodies type 3 (LKM-3) directed against family 1 uridine 5'-diphosphate-glucuronosyl-transferases (UGT-1) [3].

High impact information on UGT1A5

• We have isolated genomic DNA clones containing rat UDP-glucuronosyltransferase family 1 (UGT1) sequences and have shown drug-responsive and tissue-specific alternative expression of multiple first exons (Emi, Y., Ikushiro, S., and Iyanagi, T. (1995) J. Biochem. (Tokyo) 117, 392-399) [4].
• A novel complex locus UGT1 encodes human bilirubin, phenol, and other UDP-glucuronosyltransferase isozymes with identical carboxyl termini [5].
• 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 [5].
• The relationships of the exons 1 to each other are as follows: UGT1A2p through UGT1A5 comprises a cluster A that is 87-92% identical, and UGT1A7 through UGT1A13p comprises a cluster B that is 67-91% identical [6].
• Therefore, N-glucuronidation of 1- and 2-naphthylamine (1-NA and 2-NA),4-aminobiphenyl(4-ABP) and their N-hydroxy derivatives was investigated using rat and human liver microsomes and V79 cell-expressed phenol UDP-glucuronosyltransferases (UGT) of the UGT1 gene complex [7].

Biological context of UGT1A5

• The deduced amino acid sequence of the cDNA is 90% similar in sequence to that of a previously characterized form, UGT1A4 and to that of a third form, UGT1A5 whose function in unknown [8].
• We have established that the nucleotide sequence upstream of the UGT1A5 exon 1 is an ineffective promoter, correlating with the lack of substantial expression of this UGT in human tissues [9].
• Each isoform of UGT1 results from differential splicing of exon1s to common exon 2-5, and has an unique spectrum of substrate specificity [10].
• From linkage analyses of the three-point cross test using Elo and En-1 as marker genes, the bilirubin UDPGT gene was mapped at position 37 on chromosome 1 [11].

Anatomical context of UGT1A5

• Low-level UGT1A5 expression was also found in HepG2 and Caco-2 cells as well as human liver [12].
• We have now detected a low basal level of UGT1A5 expression in cultured human hepatocytes, and treatment with rifampicin or 3-methylcholanthrene increased the level of UGT1A5 mRNA [12].

Associations of UGT1A5 with chemical compounds

• Recombinant UGT1A5, expressed in baculovirus-infected insect cells, exhibited very low rates of 4-methylumbelliferone and scopoletin glucuronidation, whereas 1-hydroxypyrene was a much better substrate for it [12].
• However, replacing the first 110 amino acids of UGT1A5, a region that may be involved in substrate binding, with the counterpart segment from UGT1A4 did not increase the 4-aminobiphenyl glucuronidation activity [12].
• Stably expressed human and rat phenol UDP-glucuronosyltransferases (UGTs) of the UGT1 complex (HlugP1, HlugP4 and 3-methylcholanthrene-inducible rat UGT1A1, the latter considered to be an orthologous enzyme to HlugP1) have been used to investigate the role of UGTs in paracetamol glucuronidation [13].
• Other UGT1 and UGT2 enzymes seem to be responsible for the rest of the troglitazone glucuronidation in humans [14].
• Inhibitions obtained with chemicals or drugs glucuronidated by either UGT1 or UGT2 families (1-naphtol, 4-hydroxybiphenyl, carvacrol, n-propylgallate, ketoprofen, chloramphenicol, acetylsalicylic acid) indicated that at least two UGT isoforms are involved in propofol glucuronidation [15].

Other interactions of UGT1A5

• The expression of all the UGT1A isoforms, apart from UGT1A5, has been reported previously [12].
• Full-length UGT1A5 cDNA was isolated from Caco-2 cells that had been transfected with the pregnane X receptor and treated with rifampicin [12].
• To this end, we have isolated the UGT1A3, UGT1A4, and UGT1A5 proximal promoters and begun to investigate the regulatory elements necessary for activity in vitro [9].

Analytical, diagnostic and therapeutic context of UGT1A5

• PCR and Western blots confirmed the presence and expression of UGT1 in liver [16].
• METHODS: Enzyme-linked immunosorbent assay (ELISA) and Western blot were performed using baculovirus-generated human UGT-1.1 and -1.6 and rabbit UGT-1 [3].
• Sera from italian patients with HDV and patients with AIH type 2 recognized all three recombinant UGT-1 [3].

References