Regulation of CYP3A4 by the bile acid receptor FXR: evidence for functional binding sites in the CYP3A4 gene.

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Gnerre C, Blattler S, Kaufmann MR, Looser R, Meyer UA

Regulation of CYP3A4 by the bile acid receptor FXR: evidence for functional binding sites in the CYP3A4 gene.

Pharmacogenetics. 2004 Oct;14(10):635-45.

PubMed ID

15454728 [ View in PubMed

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Abstract

CYP3A4, the most abundant cytochrome P450 in human liver, is responsible for the metabolism of numerous xenobiotics and endobiotics. CYP3A4 expression is highly variable and is induced by numerous compounds of exogenous and endogenous origin, including elevated concentrations of secondary bile acids via the pregnane X receptor (PXR). We show that physiological concentrations of the primary bile acid chenodeoxycholic acid regulate the expression of CYP3A4 via the bile acid receptor FXR. Experiments performed in vitro in different cell culture systems, gel-mobility shift assays and experiments performed in vivo in transgenic mice lacking FXR or PXR and treated with the synthetic FXR agonist GW4064 were undertaken to study the implication of FXR in the regulation of CYP3A. Our data provide evidence for the presence of two functional FXR recognition sites located in a 345-bp element within the 5'-flanking region of CYP3A4. Mutational analysis of these sites and experiments in transgenic mice lacking FXR or PXR support the relevance of FXR activation for CYP3A regulation. Thus, whereas elevated concentrations of precursors of bile acids and secondary bile acids induce CYP3A via PXR, primary bile acids can modulate the expression of CYP3A via FXR. These findings may explain elevated CYP3A expression in cholestasis and part of the variability of drug responsiveness and toxicity between individuals.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Chenodeoxycholic acid	Cytochrome P450 3A4	Protein	Humans	Unknown	Substrate	Details