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Vol. 63, Issue 5, 1180-1189, May 2003
and Hepatocyte Nuclear Factor-3
Departamento de Bioquímica, Facultad de Medicina,
Universidad de Valencia, Valencia, Spain (C.R.-A., R.B., R.J., J.V.C.);
Unidad de Hepatología Experimental, Centro de
Investigación, Hospital Universitario La Fé, Valencia,
Spain (M.J.G.-L., J.V.C.); and Division of Molecular Toxicology,
Institute of Environmental Medicine, Karolinska Institute, Stockholm,
Sweden (N.T., M.I.-S.)
Cytochrome P450 3A4 (CYP3A4) is involved in the metabolism of more than
50% of currently used therapeutic drugs, yet the mechanisms that
control CYP3A4 basal expression in liver are poorly
understood. Several putative binding sites for CCAAT/enhancer-binding
protein (C/EBP) and hepatic nuclear factor 3 (HNF-3) were found by
computer analysis in CYP3A4 promoter. The use of
reporter gene assays, electrophoretic mobility shift assays, and
site-directed mutagenesis revealed that one proximal and two distal
C/EBP
binding sites are essential sites for the
trans-activation of CYP3A4 promoter. No
trans-activation was found in similar reporter gene
experiments with a HNF-3
expression vector. The relevance of these
findings was further explored in the more complex DNA/chromatin
structure within endogenous CYP3A4 gene. Using
appropriate adenoviral expression vectors, we found that both hepatic
and nonhepatic cells overexpressing C/EBP had increased
CYP3A4 mRNA levels, but no effect was observed when
HNF-3 was overexpressed. In contrast, overexpression of HNF-3
simultaneously with C/EBP resulted in a greater activation of the
CYP3A4 gene. This cooperative effect was
hepatic-specific and also occurred in CYP3A5 and
CYP3A7 genes. To investigate the mechanism for HNF-3
action, we studied its binding to CYP3A4 promoter and
the effect of the deacetylase inhibitor trichostatin A. HNF-3 was
able to bind CYP3A4 promoter at a distal position, near
the most distal C/EBP binding site. Trichostatin A increased C/EBP effect but abolished HNF-3 cooperative action. These
findings revealed that C/EBP and HNF-3 cooperatively regulate
CYP3A4 expression in hepatic cells by a mechanism that
probably involves chromatin remodeling.
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