Regulation of CYP3A5 by glucocorticoids and cigarette smoke in human lung-derived cells.

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Hukkanen J, Vaisanen T, Lassila A, Piipari R, Anttila S, Pelkonen O, Raunio H, Hakkola J

Regulation of CYP3A5 by glucocorticoids and cigarette smoke in human lung-derived cells.

J Pharmacol Exp Ther. 2003 Feb;304(2):745-52.

PubMed ID

12538830 [ View in PubMed

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Abstract

CYP3A5 is the major CYP3A form in the human lung, and it is inducible by dexamethasone in the human A549 lung adenocarcinoma cell line. In the present study, we characterized the nature and mechanism of this induction process. The induction of CYP3A5 mRNA was assessed by quantitative reverse transcriptase-polymerase chain reaction in A549 cells. About 4-fold induction was detected by nanomolar concentrations of dexamethasone and also by budenoside and beclomethasone dipropionate, glucocorticoids used for the inhalation treatment of bronchial asthma, whereas the CYP3A4 inducers mifepristone (RU486), rifampicin, clotrimazole, and nifedipine were without effect. The glucocorticoid induction was blocked by the glucocorticoid receptor (GR) antagonist RU486. In transient transfection assays to A549 cells, CYP3A5 5' regulatory region was activated by the dexamethasone treatment. In contrast, dexamethasone was unable to induce CYP3A5 transcription in GR-deficient COS-1 cells, but the induction could be achieved after GR cotransfection. The CYP3A5 expression was measured in alveolar macrophages from patients with respiratory diseases. The CYP3A5 expression level was decreased by smoking, but glucocorticoid therapy had no statistically significant effect. In conclusion, CYP3A5 is induced in the A549 cells by glucocorticoids through a GR-mediated pathway, whereas smoking may be able to depress CYP3A5 expression.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Beclomethasone dipropionate	Cytochrome P450 3A5	Protein	Humans	Unknown	Inducer	Details
Dexamethasone	Cytochrome P450 3A5	Protein	Humans	Unknown	Substrate Inducer	Details
Dexamethasone acetate	Cytochrome P450 3A5	Protein	Humans	Unknown	Substrate 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
Budesonide	Approved	CYP3A5	1577	upregulated	Budesonide results in increased expression of CYP3A5 mRNA	7q22.1
Dexamethasone	Approved Investigational Vet Approved	CYP3A5	1577	upregulated	Dexamethasone results in increased expression of CYP3A5 mRNA	7q22.1