Differential Expression of theUGT1ALocus in Human Liver, Biliary, and Gastric Tissue: Identification ofUGT1A7andUGT1A10Transcripts in Extrahepatic Tissue

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.