Differential Expression of the UGT1A Locus in Human Liver, Biliary, and Gastric Tissue: Identification ofUGT1A7 and UGT1A10 Transcripts in Extrahepatic Tissue

  1. Christian P. Strassburg1,
  2. Karl Oldhafer2,
  3. Michael P. Manns3 and
  4. Robert H. Tukey1
  1. 1University of California, San Diego, Department of Pharmacology, Cancer Center, La Jolla, California 92093-0636 (C.P.S., R.H.T.), and Departments of 2Abdominal and Transplant Surgery (K.O.) and3Gastroenterology and Hepatology (M.P.M.), Medizinische Hochschule Hannover, 30625 Hannover, Germany

    Abstract

    Family 1 UDP-glucuronosyltransferases (UGTs) (UGT1A) are encoded by a locus that predicts the existence of at least nine individual proteins. The different proteins are generated by exon-sharing, which results in the production of a family of proteins that contain identical, 245-amino acid, carboxyl-terminal domains and an amino-terminal region of approximately 280 amino acids. The diversity of theUGT1A locus suggests the existence of complex regulation, most likely designed to account for the variable and specific glucuronidation requirements. However, the tissue-specific and extrahepatic regulation of the complete UGT1A locus has not been defined to date. In this study, quantitative duplex reverse transcription-polymerase chain reaction was used to analyze UGT1A RNA expression in 16 hepatic, four biliary, and two gastric human tissue specimens. UGT1A3 and UGT1A6 were found to be expressed in the three tissues, whereas UGT1A5 and UGT1A8 were not expressed. Hepatocellular and biliary tissue expressed UGT1A1 and UGT1A4 but hepatocellular tissue uniquely expressed UGT1A9, whereas biliary tissue expressed UGT1A10. In contrast to hepatocellular tissue, gastric tissue expressed UGT1A7 in addition to UGT1A10. The expression of UGT1A9 in hepatic tissue, UGT1A7 in gastric tissue, and UGT1A10 in biliary and gastric tissue provides evidence for the selective regulation of theUGT1A locus in hepatic and extrahepatic tissues. The newly identified UGT1A7 and UGT1A10 transcripts were cloned and found to be 95.86% identical. Sequence analysis confirmed two proteins with divergent amino termini of 285 residues and identical carboxyl termini of 245 residues. This study provides evidence for hepatic and extrahepatic regulation of the human UGT1A locus and identifies two novel extrahepatic transcripts of the UGT1A family.

    Footnotes

    • Send reprint requests to: Robert H. Tukey, Ph.D., University of California, San Diego, Department of Pharmacology, La Jolla, CA 92093-0636.

    • ↵1 A nomenclature system for the UGT1A proteins is based on recommendations made at the 7th International Workshop on Glucuronidation and the Glucuronosyltransferases, University of Iowa, Iowa City, IA, May 19–22, 1996. The identification of the locus has been described, with the flanking exon 1 sequences assigned in alphabetical order. For example, the first six common functional exon sequences were originally designated UGT1A, UGT1BP, UGT1C, UGT1D, UGT1E, and UGT1F. The nomenclature that is recommended identifies the proteins as UGT1A1, UGT1A3, UGT1A4, UGT1A5, and UGT1A6, respectively (9). UGT1BP does not contain an open reading frame and is felt to be a pseudogene. Additional exon sequences have recently been identified and deposited in GenBank (Ida Owens, National Institutes of Health, personal communication); those proteins would in turn be classified based on their exon locations within the locus. In this manuscript, we classify the respective RNAs in the same way as in the recommended classification of the proteins. To date, 12 flanking exon 1 sequences have been identified, nine of which could encode functional proteins. These RNAs and the proteins that they encode are designated UGT1A1 through UGT1A10, corresponding to their respective locations in the UGT1A locus.

    • A portion of this work was presented at the 7th International Workshop on Glucuronidation and the Glucuronosyltransferases, University of Iowa, Iowa City, IA, May 19–22, 1996. This work was supported in part by Deutsche Forschungsgemeinschaft Grant Str493/2–1 (C.P.S.) and United States Public Health Service Grant GM49135 (R.H.T.).

    • Abbreviations:
      UGT
      UDP-glucuronosyltransferase
      DRT
      duplex reverse transcription
      PCR
      polymerase chain reaction
      bp
      base pair(s)
      dNTP
      deoxynucleoside triphosphate
      RT
      reverse transcription
      • Received March 19, 1997.
      • Accepted April 21, 1997.
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    1. Molecular Pharmacology August 1, 1997 vol. 52 no. 2 212-220
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