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Vol. 53, Issue 6, 1027-1033, June 1998
Is a Regulator of the UDP Glucuronosyltransferase
UGT2B1 Gene
Department of Clinical Pharmacology, Flinders University School of
Medicine, Flinders Medical Centre, Bedford Park, South Australia, 5042, Australia (A.J.H., P.I.M.),
Institute of Molecular Biology, Academia
Sinica, Nankang, Taipei, Taiwan (Y.-H.L.),
ABL-Basic Research Program,
National Cancer Institute-Frederick Cancer Research and Development
Center, Federick, Maryland, 21702-1201 (E.S.), and
Laboratory of
Metabolism, National Cancer Institute, National Institutes of Health,
Bethesda, Maryland, 20891 (F.J.G.)
The rat UDP glucuronosyltransferase, UGT2B1, is expressed in the liver
where it glucuronidates steroids, environmental toxins, and
carcinogens. A region between 
88 and 111 base pairs upstream from
the UGT2B1 gene transcription start site contains a
CCAAT enhancer binding protein (C/EBP)-like element and was previously shown by Dnase I footprint analysis to bind to proteins in both rat
liver and human hepatoma (HepG2) cell nuclear extracts. In this study,
the importance of this region in the regulation of the
UGT2B1 gene was assessed by functional and DNA binding
assays. Varying lengths of the UGT2B1 gene promoter,
with and without the C/EBP-like element, were fused to the
chloramphenicol acetyltransferase reporter gene and transfected into
HepG2 cells. Transcriptional activity of the UGT2B1 promoter construct
containing the C/EBP-like element was strongly elevated in the presence
of a cotransfected C/EBP
expression vector. In contrast, no change
was observed when an expression vector encoding C/EBP
was
cotransfected with the UGT2B1 promoter constructs. Introduction of
point mutations into the C/EBP-like element prevented any
C/EBP-mediated increase in chloramphenicol acetyltransferase
activity. Gel shift analyses demonstrated that the C/EBP-like element
binds a complex of nuclear proteins present in both HepG2 cells and rat
liver. The presence of C/EBP in this complex was confirmed by
supershift analysis with antiserum to this factor. These data strongly
suggest that the liver-enriched factor C/EBP binds to, and
activates, the UGT2B1 gene promoter. The importance of
C/EBP in the regulation of the homologous mouse
UGT2B1 gene was also assessed in vivo. Transcripts homologous to UGT2B1 were detected in the livers of mice
containing intact c/ebp and c/ebp
genes and in mice containing a homozygous null mutation in the
c/ebp gene. In contrast, these transcripts were not
detected in mice with a disrupted hepatic c/ebp gene.
These data extend the findings with the rat UGT2B1 gene
promoter and establish that C/EBP, but not C/EBP, is an essential
transcriptional regulator of the homologous UGT2B1 gene in the mouse.
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