Glucocorticoid-mediated induction of CYP3A4 is decreased by disruption of a protein: DNA interaction distinct from the pregnane X receptor response element.

Article Details

Citation

El-Sankary W, Bombail V, Gibson GG, Plant N

Glucocorticoid-mediated induction of CYP3A4 is decreased by disruption of a protein: DNA interaction distinct from the pregnane X receptor response element.

Drug Metab Dispos. 2002 Sep;30(9):1029-34.

PubMed ID
12167569 [ View in PubMed
]
Abstract

CYP3A4 is the most abundant cytochrome P450 (P450) in human liver, comprising approximately 30% of the total liver P450 content. This enzyme has an important role in steroid catabolism and metabolism of foreign compounds, with the majority of pharmaceutical compounds being substrates for CYP3A4. The molecular mechanisms that underlie transcriptional activation of CYP3A4 are complex with many steroid hormone nuclear receptors, including glucocorticoid receptor, pregnane X receptor (PXR), vitamin D receptor, and constitutive androstane receptor, playing roles. Nowhere is this more evident than in the induction of CYP3A4 gene expression by glucocorticoids. CYP3A genes lack a consensus glucocorticoid receptor response element and yet are highly induced by classical glucocorticoids such as hydrocortisone and dexamethasone. Recent evidence has demonstrated that glucocorticoids are ligands for the orphan nuclear receptor PXR, and induction of CYP3A genes by glucocorticoids may occur primarily through PXR interactions. In this paper, we present a mutant that disrupts a hepatocyte-nuclear-factor-3/CCAAT-enhancer binding protein alpha binding site in the CYP3A4 proximal promoter. This mutation disrupts induction of a reporter gene construct by the glucocorticoids dexamethasone and hydrocortisone; yet induction by the potent PXR ligand rifampicin is unaffected. Such data provides strong evidence that glucocorticoids induce CYP3A4 gene expression both through the established PXR-dependent pathway but also through a PXR-independent pathway.

DrugBank Data that Cites this Article

Drug Enzymes
DrugEnzymeKindOrganismPharmacological ActionActions
FluorometholoneCytochrome P450 3A4ProteinHumans
Unknown
Substrate
Inducer
Details
HydrocortamateCytochrome P450 3A4ProteinHumans
Unknown
Inducer
Details
HydrocortisoneCytochrome P450 3A4ProteinHumans
Unknown
Substrate
Inducer
Details
Drug Interactions
DrugsInteraction
Flunisolide
Methimazole
The metabolism of Flunisolide can be decreased when combined with Methimazole.
Flunisolide
Nilotinib
The metabolism of Flunisolide can be decreased when combined with Nilotinib.
Flunisolide
Terfenadine
The metabolism of Flunisolide can be decreased when combined with Terfenadine.
Flunisolide
Ergotamine
The metabolism of Flunisolide can be decreased when combined with Ergotamine.
Flunisolide
Conivaptan
The metabolism of Flunisolide can be decreased when combined with Conivaptan.