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.
Footnotes
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This work was funded in part by grants to J.Hu. from the Finnish Cultural Foundation, the Northern Finland Cancer Society, the Finnish Drug Research Foundation, the Finnish Cancer Foundation, the Foundation of University Pharmacy, the Research and Science Foundation of Farmos, and the Emil Aaltonen Foundation and to O.P. from TEKES (Technology Development Center, Finland).
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DOI: 10.1124/jpet.102.038208
- Abbreviations:
- P450
- cytochrome P450
- B[a]P
- benzo[a]pyrene
- CAR
- constitutively active receptor
- GR
- glucocorticoid receptor
- PAH
- polycyclic aromatic hydrocarbon
- PXR
- pregnane X receptor
- RT-PCR
- reverse transcriptase-polymerase chain reaction
- RU486
- mifepristone
- PCR
- polymerase chain reaction
- Tamra
- 5-carboxytetramethylrhodamine
- ANOVA
- analysis of variance
- GRE
- glucocorticoid response elements
- Received May 2, 2002.
- Accepted November 6, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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