Regulation of CYP3A genes by glucocorticoids in human lung cells.
Article Details
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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]
- 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 UnknownSubstrateInducerDetails Methylprednisolone Cytochrome P450 3A Subfamily (Protein Group) Protein group Humans UnknownSubstrateInducerDetails Prednisolone phosphate Cytochrome P450 3A Subfamily (Protein Group) Protein group Humans UnknownInducerDetails - 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