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ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Regulation of CYP3A5 by Glucocorticoids and Cigarette Smoke in Human Lung-Derived Cells

Department of Pharmacology and Toxicology, University of Oulu, Finland (J.Hu., T.V., A.L., O.P., J.Ha.); Department of Internal Medicine, Lapland Central Hospital, Rovaniemi, Finland (J.Hu.); Finnish Institute of Occupational Health, Helsinki, Finland (R.P., S.A.); and Department of Pharmacology and Toxicology, University of Kuopio, Finland (H.R.)

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.

Address correspondence to: Jukka Hakkola, Department of Pharmacology and Toxicology, University of Oulu, P.O. Box 5000, FIN-90014 Oulun yliopisto, Finland. E-mail: jukka.hakkola{at}oulu.fi

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