Skip to main content
SpringerLink
Log in

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

  • Published:
Inflammation Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Eras, J., and M. Perazella. 2001. NSAIDs and the kidney revisited: Are selective cyclooxygenase-2 inhibitors safe? [Review]. Am. J. Med. Sci. 321:181–190.

    Article  PubMed  Google Scholar 

  2. Mukherjee, D., S. Nissen, and E. J. Topol. 2001. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA 286:954–959.

    PubMed  Google Scholar 

  3. Smith, W. L., and D. L. DeWitt. 1996. Prostaglandin endoperoxide H synthases-1 and -2 [Review]. Adv. Immunol. 62:167– 215.

    PubMed  Google Scholar 

  4. Merck Announces Voluntary Worldwide Withdrawal of Vioxx [News Release]. September 30, 2004. Merck & Co., Whitehouse Station, NJ.

  5. Pfizer Provides Information to Healthcare Professionals About its Cox-2 Medicine Bextra® (Valdecoxib) [News Release]. October 15, 2004. Pfizer, New York.

  6. Smith, W. L., R. M. Garavito, and D. L. DeWitt. 1996. Prostaglandin endoperoxide H synthases (cyclooxygenases)-1 and -2 [Review]. J. Biol. Chem. 271:33157–33160.

    Article  PubMed  Google Scholar 

  7. Subongkot, S., D. Frame, W. Leslie, and D. Drajer. 2003. Selective cyclooxygenase-2 inhibition: A target in cancer prevention and treatment [Review]. Pharmacotherapy 23:9–28.

    Article  PubMed  Google Scholar 

  8. Müller, G. 2003. Medicinal chemistry of target family-directed masterkeys [Review]. Drug Discov. Today 8:681–691.

    Article  PubMed  Google Scholar 

  9. Knudsen, J. F., G. H. Sokol, and L. R. Cantilena. 2003. Structure-activity relationships as predictors of adverse drug events (ADEs). Clin. Pharmacol. Ther. 73:39 (Abstract).

    Google Scholar 

  10. Physicians’ Desk Reference, 55th ed., 2001. Medical Economics Company, Montvale, NJ, 2903.

  11. DuBose, T. D., and L. L. Hamm (eds.). 2002. Acid–Base and Electrolyte Disorders. A Companion to Brenner and Rector’s The Kidney, Saunders, Philadelphia.

    Google Scholar 

  12. Knudsen, J. F., U. Carlsson, P. Hammarstrüm, G. H. Sokol, and L. R. Cantilena. 2004. Cox-2 inhibitors and carbonic anhydrase activity.Clin. Pharmacol. Ther. 75:44. Abstract.

    Google Scholar 

  13. Belsky, H. 1953. Use of new oral diuretic, diamox, in congestive heart disease. N. Engl. J. Med. 249:140–143.

    PubMed  Google Scholar 

  14. Maren, T. H. 1967. Carbonic anhydrase: Chemistry, physiology, and inhibition [Review]. Physiol. Rev. 47:595–781.

    PubMed  Google Scholar 

  15. Beyer, K., and J. Baer. 1961. Physiological basis for the action of newer diuretic agents. Pharmacol. Rev. 40:517– 562.

    Google Scholar 

  16. Chegwidden, W. R., and N. D. Carter. 2000. Introduction to the carbonic anhydrases. In: The Carbonic Anhydrases. New Horizons, W. R. Chegwidden, N. D. Carter, and Y. H. Edwards, eds. Birkháuser Verlag, Basel, Switzerland, pp. 13–28.

    Google Scholar 

  17. Hsu, H. H., and B. G. Abbo. 2004. Role of bicarbonate/CO2 buffer in the initiation of vesicle mediated calcification: Mechanisms of aortic calcification related to atherosclerosis. Biochim. Biophys. Acta. 1690:118–123.

    PubMed  Google Scholar 

  18. Saini, S. S., D. L. Gessell-Lee, and J. W. Peterson. 2003. The Cox-2 specific inhibitor celecoxib inhibits adenylyl cyclase. Inflammation 27:79–88.

    Article  PubMed  Google Scholar 

  19. Moore, A. R., and D. A. Willoughby. 1995. The role of cAMP regulation in controlling inflammation [Review]. Clin. Exp. Immunol. 101:387–389.

    PubMed  Google Scholar 

  20. Weber, A., A. Casini, A. Heine, D. Kuhn, C. T. Supuran, A.Scozzafava, and G. Klebe. 2004. Unexpected nanomolar inhibition of carbonic anhydrase by COX-2-selective celecoxib: New pharmacological opportunities due to related binding site recognition. J. Med. Chem. 47:550–557.

    Article  PubMed  Google Scholar 

  21. Rickli, E. E., S. A. Ghazanfar, B. H. Gibbons, and J. T. Edsall. 1964. Carbonic anhydrases from human erythrocytes. Preparation and properties of two enzymes. J. Biol. Chem. 239:1065–1078.

    PubMed  Google Scholar 

  22. Freskgård, P. O., U. Carlsson, L. G. Mårtensson, and B. H. Jonsson. 1991. Folding around the C-terminus of human carbonic anhydrase II. Kinetic characterization by use of a chemically reactive SH-group introduced by protein engineering. FEBS Lett. 289:117–122.

    Article  PubMed  Google Scholar 

  23. Mårtensson, L. G., B. H. Jonsson, P. O. Freskgård, A. Kihlgren, M. Svensson, and U. Carlsson. 1993. Characterization of folding intermediates of human carbonic anhydrase II: Probing substructure by chemical labeling of SH groups introduced by site-directed mutagenesis. Biochemistry 32:224–231.

    Article  PubMed  Google Scholar 

  24. Zhu, J., X. Song, H. P. Lin, D. C. Young, S. Yan, V. E. Marquez, and C. S. Chen. 2002. Using cyclooxygenase-2 inhibitors as molecular platforms to develop a new class of apoptosis-inducing agents. J. Natl. Cancer Inst. 94:1745–1757.

    PubMed  Google Scholar 

  25. Maderna, P., and C. Godson. 2003. Phagocytosis of apoptotic cells and the resolution of inflammation. Biochim. Biophys. Acta. 1639:141–151.

    PubMed  Google Scholar 

  26. McCormack, K., and K. Brune. 1991. Dissociation between the antinociceptive and anti-inflammatory effects of the nonsteroidal anti-inflammatory drugs. A survey of their analgesic efficacy. Drugs 41:533–547.

    PubMed  Google Scholar 

  27. Song, X., H. P. Lin, A. J. Johnson, P. H. Tsang, Y. T. Yang, and S. K. Kulp. 2002. Cyclooxygenase-2, a player or spectator in cyclooxygenase-2 inhibitor-induced apoptosis in prostatic cancer cells. J. Natl. Cancer Inst}. 94:585–591.

    PubMed  Google Scholar 

  28. Mori, M., R. J. Staniunas, G. F. Barnard, J. M. Jessup, G. D. Steele Jr., and L. B. Chen. 1993. The significance of carbonic anhydrase expression in human colorectal cancer. Gastroenterology 105:820–826.

    PubMed  Google Scholar 

  29. Parkkila, S., A. K. Parkkila, T. Juvonen, V. P. Lehto, and H. Rajaniemi. 1995. Immunohistochemical demonstration of the carbonic anhydrase isoenzymes I and II in pancreatic tumors. Histochem. J. 27:133–138.

    PubMed  Google Scholar 

  30. Parkkila, S., H. Rajaniemi, A. K. Parkkila, J. Kivelá, A. Waheed, S. Pastoreková, J. Pastorek, and W. S. Sly. 2000. Carbonic anhydrase inhibitor suppresses invasion of renal cancer cells in vitro. Proc. Natl. Acad. Sci. U.S.A. 97:2220–2224.

    Article  PubMed  Google Scholar 

  31. Puscas, I., M. Coltau, and R. Pasca. 1996. Nonsteroidal anti-inflammatory drugs activate carbonic anhydrase by a direct mechanism of action. J. Pharmacol. Exp. Ther. 277:1464–1466.

    PubMed  Google Scholar 

  32. Paroutis, P., N. Touret, and S. Grinstein. 2004. The pH of secretory pathways: Measurement, determinants and regulation. Physiology 19:207–215.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Clinical Pharmacology and Medical Toxicology, Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland

    James F. Knudsen, Gerald H. Sokol & Louis R. Cantilena

  2. IFM-Department of Chemistry, Linköping University, Linköping, Sweden

    Uno Carlsson & Per Hammarström

  3. New Hope Cancer Center, Hudson, Florida

    Gerald H. Sokol

  4. Box 550, Smithsburg, MD, 21783

    James F. Knudsen

Authors
  1. James F. Knudsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Uno Carlsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Per Hammarström
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gerald H. Sokol
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Louis R. Cantilena
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to James F. Knudsen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Knudsen, J.F., Carlsson, U., Hammarström, P. et al. The Cyclooxygenase-2 Inhibitor Celecoxib Is a Potent Inhibitor of Human Carbonic Anhydrase II. Inflammation 28, 285–290 (2004). https://doi.org/10.1007/s10753-004-6052-1

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10753-004-6052-1

Key Words

Search

Navigation