Regulation of CYP3A genes by glucocorticoids in human lung cells.

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Roberts JK, Moore CD, Romero EG, Ward RM, Yost GS, Reilly CA

Regulation of CYP3A genes by glucocorticoids in human lung cells.

F1000Res. 2013 Aug 13;2:173. doi: 10.12688/f1000research.2-173.v2. eCollection 2013.

PubMed ID

24555085 [ View in PubMed

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Abstract

Inhaled glucocorticoids are the first-line treatment for patients with persistent asthma. However, approximately thirty percent of patients exhibit glucocorticoid insensitivity, which may involve excess metabolic clearance of the glucocorticoids by CYP3A enzymes in the lung. CYP3A4, 3A5, and 3A7 enzymes metabolize glucocorticoids, which in turn induce CYP3A genes. However, the mechanism of CYP3A5 mRNA regulation by glucocorticoids in lung cells has not been determined. In hepatocytes, glucocorticoids bind to the glucocorticoid receptor (GR), which induces the expression of the constitutive androstane receptor or pregnane X receptor; both of which bind to the retinoid X receptor alpha, leading to the induction of CYP3A4, 3A5, and 3A7. There is also evidence to suggest a direct induction of CYP3A5 by GR activation in liver cells. In this study, these pathways were evaluated as the mechanism for CYP3A5 mRNA induction by glucocorticoids in freshly isolated primary tracheal epithelial, adenocarcinomic human alveolar basal epithelial (A549), immortalized bronchial epithelial (BEAS-2B), primary normal human bronchial/tracheal epithelial (NHBE), primary small airway epithelial (SAEC), and primary lobar epithelial lung cells. In A549 cells, beclomethasone 17-monopropionate ([M1]) induced CYP3A5 mRNA through the glucocorticoid receptor. CYP3A5 mRNA induction by five different glucocorticoids was attenuated by inhibiting the glucocorticoid receptor using ketoconazole, and for beclomethasone dipropionate, using siRNA-mediated knock-down of the glucocorticoid receptor. The constitutive androstane receptor was not expressed in lung cells. SAEC cells, a primary lung cell line, expressed CYP3A5, but CYP3A5 mRNA was not induced by glucocorticoid treatment despite evaluating a multitude of cell culture conditions. None of the other lung cells expressed CYP3A4, 3A5 or 3A7 mRNA. These studies demonstrate that CYP3A5 mRNA is induced by glucocorticoids in A549 cells via the glucocorticoid receptor, but that additional undefined regulatory processes exist in primary lung cells.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Budesonide	Cytochrome P450 3A Subfamily (Protein Group)	Protein group	Humans	Unknown	Substrate Inducer	Details
Methylprednisolone	Cytochrome P450 3A Subfamily (Protein Group)	Protein group	Humans	Unknown	Substrate Inducer	Details
Prednisolone phosphate	Cytochrome P450 3A Subfamily (Protein Group)	Protein group	Humans	Unknown	Inducer	Details

Pharmaco-transcriptomics

Drug	Drug Groups	Gene	Gene ID	Change	Interaction	Chromosome
Beclomethasone dipropionate	Approved Investigational	CYP3A5	1577	upregulated	Beclomethasone results in increased expression of CYP3A5 mRNA	7q22.1
Beclomethasone dipropionate	Approved Investigational	NR3C1	2908	upregulated	Beclomethasone results in increased expression of NR3C1 mRNA	5q31.3
Budesonide	Approved	CYP3A5	1577	upregulated	Budesonide results in increased expression of CYP3A5 mRNA	7q22.1
Flunisolide	Approved Investigational	CYP3A5	1577	upregulated	flunisolide results in increased expression of CYP3A5 mRNA	7q22.1
Fluticasone propionate	Approved	CYP3A5	1577	upregulated	Fluticasone results in increased expression of CYP3A5 mRNA	7q22.1
Triamcinolone	Approved Vet Approved	CYP3A5	1577	upregulated	Triamcinolone Acetonide results in increased expression of CYP3A5 mRNA	7q22.1