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Vol. 62, Issue 2, 359-365, August 2002
Department of Clinical Pharmacology and Storr Liver Unit,
University of Sydney, Westmead Millennium Institute, Westmead, New
South Wales, Australia
Cytochrome P450 3A4 (CYP3A4), the predominant P450 expressed in
adult human liver, is both constitutively expressed and
transcriptionally activated by a variety of structurally diverse
xenochemicals. In this study, we examined the role of the constitutive
androstane receptor (CAR), a member of the steroid/retinoid/thyroid
hormone receptor superfamily, in the transcriptional regulation
of CYP3A4. Herein, we demonstrate that CAR is capable of
trans-activating expression of the CYP3A4
gene, both in vitro and in vivo. Induction of CYP3A4 is
dependent on cooperativity between elements within the promoter
proximal region of the gene and the distal xenobiotic-responsive enhancer module. CAR responsiveness was shown to be primarily mediated by two high-affinity binding motifs located within the CYP3A4 gene 5'-flanking region, approximately 7720 and
150 bases upstream of the transcription initiation site. Importantly,
the human CAR response elements also mediate
trans-activation of CYP3A4 by the human
pregnane X receptor, suggesting that interplay between these receptors
is likely to be an important determinant of CYP3A4 expression.
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|
|
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