Abstract
Rofecoxib is a selective cyclooxygenase (COX)-2 inhibitor approved for the treatment of pain and inflammation in rheumatoid and osteoarthritis. Daily doses between 12.5 and 50 mg were found to reduce pain and inflammation, however, without a clear dose-effect relationship. Interestingly, rofecoxib treatment is associated with an unexpected incidence of renal adverse events compared with other COX inhibitors. Here, the effects of rofecoxib on the transcription factors nuclear factor-κB (NF-κB) and activating protein-1 (AP-1) were analyzed to find out whether transcriptional changes might explain the lack of clear dose dependency and the occurrence of renal side effects. In vitro, rofecoxib dose dependently inhibited DNA binding capacity of NF-κB at doses of 10 to 100 μM, whereas the binding activity of AP-1 was considerably increased at 100 μM. In vivo, the anti-inflammatory effect of rofecoxib was equal at 1 and 10 mg/kg, whereas 50 mg/kg caused a significant further reduction of a zymosan-induced paw edema. This was associated with a clear decrease of inducible nitric oxide synthase (iNOS) protein expression in the spinal cord at this dose. At 1 and 10 mg/kg, however, iNOS was increased but COX-2 was decreased. Thus, the expression of proinflammatory proteins was similarly inconsistent as transcription factor regulation. In conclusion, the opposite effects of rofecoxib on AP-1 and NF-κB may explain the lack of clear dose dependency with rofecoxib in clinical studies or animal experiments. The effects on AP-1 may possibly affect renal sodium transport because certain renal sodium channels are regulated through AP-1. Transcription factor regulation might therefore influence both wanted and unwanted effects of rofecoxib.
Footnotes
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This study was supported by the Deutsche Forschungsgemeinschaft (SFB 553/C6) and in part by an unrestricted grant from MSD (München, Germany).
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DOI: 10.1124/jpet.102.044016
- Abbreviations:
- COX
- cyclooxygenase
- NSAID
- nonsteroidal anti-inflammatory drug
- NF-κB
- nuclear factor-κB
- TNFα
- tumor necrosis factor-α
- AP-1
- AP, activating protein
- I-κB
- inhibitory-κB
- iNOS
- inducible nitric-oxide synthase
- AUC
- area under the curve
- HPLC
- high-performance liquid chromatography
- PGE2
- prostaglandin E2
- LPS
- lipopolysaccharide
- PBS
- phosphate-buffered saline
- CHAPS
- 3-[(3-cholamidopropyl)dimethylammonio]propanesulfonate
- DTT
- dithiothreitol
- PMSF
- phenylmethylsulfonyl fluoride
- EMSA
- electrophoretic mobility shift assay
- MOPS
- 3-(N-morpholino)propanesulfonic acid
- SSC
- standard saline citrate
- BAY M-7085
- (E)-3-(4-t-butylphenylsulfonyl)-2-propenenitril
- Received September 4, 2002.
- Accepted December 9, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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