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University of California, San Diego, Department of Pharmacology,
Cancer Center, La Jolla, California 92093-0636 (C.P.S., R.H.T.), and
Departments of
Abdominal and Transplant Surgery (K.O.) and
Gastroenterology and Hepatology (M.P.M.), Medizinische Hochschule
Hannover, 30625 Hannover, Germany
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 the UGT1A 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 the
UGT1A 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.
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