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Molecular Mechanism of Basal CYP3A4 Regulation by Hepatocyte Nuclear Factor 4: Evidence for Direct Regulation in the Intestine

Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany, and University of Tübingen, Tübingen, Germany

Cytochrome P450 3A4 plays an outstanding role in the metabolism of clinically used drugs and shows a marked interindividual variability in expression even in the absence of inducing agents. Thus, regulation of basal expression contributes considerably to variability. The nuclear receptor hepatocyte nuclear factor 4 (HNF4) was previously shown to be associated with basal hepatic CYP3A4 expression. As how HNF4 regulates basal expression of CYP3A4 still remains elusive, we systematically screened 12.5 kilobase pairs (kb) of the CYP3A4 5' upstream region for activation by the receptor in the human intestinal cell line LS174T. In this study, we newly identified two widely separated regions mediating the activation by HNF4: a far distal region at -9.0 kb and the proximal promoter region at -0.2 kb. By gel shift experiments and transient transfections, we characterized direct repeat (DR) 1-type motifs in both regions as functional HNF4 response elements. Cooperation of the two regions was shown to be required for maximal activation by HNF4. The effect of HNF4 was antagonized by chicken ovalbumin upstream promoter transcription factor II, which was shown to bind to one of the DR1 motifs. Furthermore, activation of CYP3A4 via the DR1 element in the proximal promoter depends on an additional, yet unknown, factor, which is binding at -189 base pairs. Physiological relevance of this position for activation by HNF4 in vivo is suggested by the presence of a binding activity in small intestine similar to that in LS174T cells. In summary, we here have elucidated a molecular mechanism of direct regulation of CYP3A4 by HNF4, which is probably specific for the intestine.

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