Disease relevance of UGT1A10

• Whereas UGT1A9 was not regulated, differential regulation of UGT1A7 and UGT1A10 mRNA was observed between normal oesophageal epithelium and squamous-cell carcinoma [1].
• UGT1A10 is responsible for SN-38 glucuronidation and its expression in human lung cancers [2].
• 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 [3].
• 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) [4].
• 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 [5].

High impact information on UGT1A10

• 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) [6].
• Inhibition of cellular UGT1A7 and UGT1A10 activities and of [33P]orthophosphate incorporation into immunoprecipitable proteins after exposure to curcumin or calphostin-C indicated that the isozymes are phosphorylated [7].
• UGT1A10, a newly discovered UGT1A gene product, is expressed only in biliary and not hepatocellular tissue and is also significantly down-regulated in cholangiocellular carcinoma [8].
• In Tg-UGT1 mice, the UGT1A proteins are differentially expressed in the liver and gastrointestinal tract [9].
• 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 [9].

Biological context of UGT1A10

• In summary, our results suggest gastrointestinally distributed UGT1A10 is important for detoxifying estrogens/phytoestrogens and aromatic acids with complementary activity by UGT1A7, -1A8, -1A3, and/or -1A1 evidently dependent upon phosphorylation [10].
• The kinetics of the troglitazone glucuronidation in the recombinant UGT1A10 and UGT1A1 exhibited an atypical pattern of substrate inhibition when the substrate concentration was over 200 micro M [11].
• 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 [1].
• UGT1 consists of 5 exons and has a unique gene structure [12].
• Each isoform of UGT1 results from differential splicing of exon1s to common exon 2-5, and has an unique spectrum of substrate specificity [12].

Anatomical context of UGT1A10

• In contrast, a polymorphic expression pattern of all the UGT genes was demonstrated in duodenal, jejunal, and ileal mucosa, with the exception of UGT1A10 [13].
• UGT1A10 compared with UGT1A7, -1A8, and -1A3 generally exhibited high activity toward acidic nonsteroidal anti-inflammatory drugs and natural benzaldehyde derivatives, while UGT1A3 metabolized most efficiently aromatic transcinnamic acids known to be generated from flavonoid glycosides by microflora in the lower gastrointestinal tract [10].
• Troglitazone glucuronidation in human liver and intestine microsomes: high catalytic activity of UGT1A8 and UGT1A10 [11].
• The enzyme synthesized in UGT1A10 cDNA-transfected COS-7 cells has a relative molecular mass of 56 kDa and is very active in the glucuronidation of mycophenolic acid (apparent Km of 34 microM and Vmax of 0.6 nmoles/min/mg protein) [14].
• The isoform UGT1A10, along with UGT1A7 and UGT1A8, is expressed exclusively in extrahepatic tissues, notably in the gastrointestinal tract [15].

Associations of UGT1A10 with chemical compounds

• Additionally UGT1A10-expressing cultures glucuronidated 17beta-[(14)C]estradiol, whereas cultures containing null mutants at protein kinase C sites showed no estrogen conversion [10].
• Finally UGT1A10, -1A7, -1A8, and -1A3 converted plant-based salicylic acids; methylsalicylic acid was transformed at high levels, and acetylsalicylic (aspirin) and salicylic acid were transformed at moderate to low levels [10].
• The ability of UGT1A10 to glucuronidate estrone represents only the second example of a human estrone UGT [16].
• The troglitazone glucuronosyltransferase activity in human jejunum microsomes was strongly inhibited by emodin (IC(50) = 15.6 micro M), a typical substrate of UGT1A8 and UGT1A10, rather than by bilirubin (IC(50) = 154.0 micro M) [11].
• With a Michaelis-Menten equation at 6 to 200 micro M troglitazone, the K(m) value was 11.1 +/- 5.8 micro M and the V(max) value was 33.6 +/- 3.7 pmol/min/mg protein in recombinant UGT1A10 [11].

Other interactions of UGT1A10

• In addition, the expression of extrahepatic UGT1A10 and UGT1A8 was demonstrated [16].
• In contrast to hepatocellular tissue, gastric tissue expressed UGT1A7 in addition to UGT1A10 [17].
• Differential expression of the UGT1A locus in human liver, biliary, and gastric tissue: identification of UGT1A7 and UGT1A10 transcripts in extrahepatic tissue [17].
• 6-Hydroxymelatonin was glucuronidated largely by UGT1A9 and UGT1A10 but not at all by UGT1A6 [18].

Analytical, diagnostic and therapeutic context of UGT1A10

• RESULTS: Our HPLC assay results showed that both UGT1A1 and UGT1A10 are responsible for SN-38 glucuronidation [2].
• Using the combination of photoaffinity labeling, enzymatic digestion, MALDI-TOF and LC-MS mass spectrometry, and site-directed mutagenesis, we have determined for the first time that Phe(90) and Phe(93) are directly involved in the catalytic activity of UGT1A10 toward 4-MU and pNP [19].
• Membrane preparations from human embryonic kidney 293 cells expressing either UGT1A8 or UGT1A10 were isolated and the expression of each isoform was analyzed by Western blot [20].
• To account for the difference in species- and disposition model-dependent intestinal metabolism, we probed the presence of various UGT1A isoforms in Caco-2 cells using real-time reverse transcriptase-polymerase chain reaction and, as expected, detected no UGT1A10 [21].
• High-performance liquid chromatography analysis of E2 glucuronide revealed that UGT1A10 catalyzed E2 3-O-glucuronidation but not 17-O-glucuronidation [22].

References