Inflammation

, Volume 28, Issue 5, pp 285–290

The Cyclooxygenase-2 Inhibitor Celecoxib Is a Potent Inhibitor of Human Carbonic Anhydrase II

Authors

    • Division of Clinical Pharmacology and Medical Toxicology, Department of MedicineUniformed Services University of the Health Sciences
  • Uno Carlsson
    • IFM-Department of ChemistryLinköping University
  • Per Hammarström
    • IFM-Department of ChemistryLinköping University
  • Gerald H. Sokol
    • Division of Clinical Pharmacology and Medical Toxicology, Department of MedicineUniformed Services University of the Health Sciences
    • New Hope Cancer Center
  • Louis R. Cantilena
    • Division of Clinical Pharmacology and Medical Toxicology, Department of MedicineUniformed Services University of the Health Sciences
Article

DOI: 10.1007/s10753-004-6052-1

Cite this article as:
Knudsen, J.F., Carlsson, U., Hammarström, P. et al. Inflammation (2004) 28: 285. doi:10.1007/s10753-004-6052-1

Abstract

Cyclooxygenase-2 (COX-2) is up-regulated in stromal and inflammatory cells. The inducible COX-2 isoform is expressed during inflammation, in some cancers, and in brain tissue after global and focal ischemia. Tissue acidosis is a dominant factor in inflammation, and contributes to pain and hyperalgesia. Recently, compelling epidemiological and clinical evidence has documented the COX-independent effects of some COX-2 inhibitors (i.e., celecoxib, valdecoxib, and rofecoxib); among these effects are carbonic anhydrase (CA) inhibition. Carbonic anhydrases are zinc metalloenzymes expressed in various cell types, including those of the kidney, where they act as general acid–base catalysts. The kidneys are also known to express the highest concentration of COX-2 messenger ribonucleic acid. Celecoxib, like the prototypic CA inhibitor acetazolamide, is structurally characterized by an unsubstituted sulfonamide moiety. In the present study, we report that celecoxib exhibits the characteristics of a potent CA inhibitor, showing inhibitory human carbonic anhydrase II (hCAII) activity in the nanomolar range. Valdecoxib was relatively less potent. Rofecoxib, which lacks the unsubstituted sulfonamide moiety characteristic of CA inhibitors, showed no significant hCAII inhibitory activity. The current study corroborates our earlier report of structure-activity relationships as predictors of such metabolic events as hyperchloremia, acidosis, and changes in calcium and phosphate disposition; and clinical manifestations associated with CA inhibition reported with celecoxib. These data showing inhibition of hCAII by the unsubstituted sulfonamides celecoxib and valdecoxib, but not by rofecoxib, may have important implications for the elucidation of the mechanisms of action as well as the side effects associated with COX-2 inhibitors.

Key Words

COX-2celecoxibcarbonic anhydrasebicarbonateinflammation

Copyright information

© Springer Science + Business Media, Inc. 2004