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Effects of celecoxib in young rats: Histopathological changes in tissues and alterations of oxidative stress/antioxidant defense system

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Abstract

Celecoxib is increasingly being used in children with rheumatologic complaints. Although the particular concerns about the safety of the drug, there are only a small number of published studies in children. This study was performed to investigate the effects of celecoxib on oxidative stress and antioxidant enzyme activities as well as celecoxib-induced changes in liver, kidneys and stomach of young rats. Four weeks-old Wistar albino, female rats were used. Celecoxib was given by gavage for 14 days. Control rats received only vehicle. Blood and organs were taken under pentobarbital anesthesia. Plasma malondialdehyde levels were increased by treatment. Catalase activity was increased, while glutathione peroxidase activity was decreased. Superoxide dismutase and glucose-6-phosphate dehydrogenase activities was not changed by treatment. The reduced glutathione content of kidneys were higher, while there was no significant difference in liver content, as compared with controls. Significant changes were observed in serum parameters of rats treated with celecoxib. Histopathological evaluation of organs was done by an experienced pathologist unaware of the treatment. Results of the present study indicated the alterations of oxidant/antioxidant status and histopathological changes in tissues of young rats treated with celecoxib.

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References

  • Aebi, H., Catalase in vitro. Methods Enzymol., 105, 121–126 (1984).

    Article  PubMed  CAS  Google Scholar 

  • Ahmad, S. R., Kortepeter, C., Brinker, A., Chen, M., and Beitz, J., Renal failure associated with the use of celecoxib and rofecoxib. Drug Saf., 25, 537–544 (2002).

    Article  PubMed  CAS  Google Scholar 

  • Arai, I., Hamasaka, Y., Futaki, N., Takahashi, S., Yoshikawa, K., Higuchi, S., and Otomo, S., Effect of NS-398, a new nonsteroidal anti-inflammatory agent, on gastric ulceration and acid secretion in rats. Res. Commun. Chem. Pathol. Pharmacol., 81, 259–270 (1993).

    PubMed  CAS  Google Scholar 

  • Brater, D. C., Renal effects of Cyclooxygenase-2 selective inhibitors. J. Pain Symptom Manage., 23, S15–S20 (2002).

    Article  PubMed  CAS  Google Scholar 

  • Burak Cimen, M. Y., Cimen, O. B., Eskandari, G., Sahin, G., Erdoğan, C., and Atik, U., In vivo effects of meloxicam, celecoxib, and ibuprofen on free radical metabolism in human erythrocytes. Drug Chem. Toxicol., 26, 169–176 (2003).

    Article  PubMed  CAS  Google Scholar 

  • Chakraborty, S., Kar, S. K., Roy, K., and Sengupta, C., Exploring effects of different nonsteroidal antiinflammatory drugs on malondialdehyde profile. Acta Pol. Pharm., 63, 83–88 (2006).

    PubMed  CAS  Google Scholar 

  • Chang, H., Yen, J. H., and Yin, C. L., Celecoxib stimulates reparatory burst through pertussis toxin-sensitive Gprotein, a possible signal for beta 2-integrin expression on human neutrophils. Eur. J. Pharmacol., 484, 29–39 (2004).

    Article  Google Scholar 

  • Crofford, L. J., COX-1 and COX-2 tissue expression: implication and prediction. J. Rheumatol. Suppl., 49, 15–19 (1997).

    PubMed  CAS  Google Scholar 

  • De Ferreyra, E. C., Bernacchi, A. S., and Castro, J. A., Increased glutathione (GSH) content in livers of control and carbon tetrachloride poisoned rats treated with the anticalmodulin drug trifluoperazine (TFP). Res. Commun. Chem. Pathol. Pharmacol., 53, 399–402 (1986).

    PubMed  Google Scholar 

  • Demircan, B., Celik, G., Suleyman, H., and Akcay, F., Effects of indomethacin, celecoxib and meloxicam on glutathione, malondialdehyde and myeloperoxidase in rat gastric tissue. Pain Clin., 4, 383–388 (2005).

    Article  Google Scholar 

  • Ferraz, J. G., Sharkey, K. A., Reuter, B. K., Asfaha, S., Tigley, A. W., Brown, M. L., and McKnight, W. L., Induction of cyclooxygenase 1 and 2 in the rat stomach during endotoxemia: role in resistance to damage. Gastroenterology, 113, 195–204 (1997).

    Article  PubMed  CAS  Google Scholar 

  • Foeldvari, I., Szer, I. S., Zemel, L. S., Lovell, D. J., Giannini, E. H., Robbins, J. L., West, C. R., Steidle, G., Krishnaswami, S., and Bloom, B. J., A prospective study comparing celecoxib with naproxen in children with juvenile rheumatoid arthritis. J. Rheumatol., 36, 174–182 (2009).

    PubMed  Google Scholar 

  • Gambero, A., Maróstica, M., Becker, T. L., and Pedrazzoli, J. Jr., Effect of different cyclooxygenase inhibitors on gastric adaptive cytoprotection induced by 20% ethanol. Dig. Dis. Sci., 52, 425–433 (2007).

    Article  PubMed  CAS  Google Scholar 

  • Gupta, S., Sarotra, P., Aggarwal, R., Dutta, N., and Agnihotri, N., Role of oxidative stress in celecoxib-induced renal damage in wistar rats. Dig. Dis. Sci., 52, 3092–3098 (2007).

    Article  PubMed  CAS  Google Scholar 

  • Hao, C. M., Yull, F., Blackwell, T., Kömhoff, M., Davis, L. S., and Breyer, M. D., Hypertension and cyclooxygenase-2 inhibitors: target the renal medulla. J. Clin. Invest., 106, 973–982 (2000).

    Article  PubMed  CAS  Google Scholar 

  • Kargman, S., Charleson, S., Cartwright, M., Frank, J., Riendeau, D., Mancini, J., Evans, J., and O’Neill, G., Characterization of Prostaglandin G/H Synthase 1 and 2 in rat, dog, monkey, and human gastrointestinal tracts. Gastroenterology, 111, 445–454 (1996).

    Article  PubMed  CAS  Google Scholar 

  • Kirkova, M., Alexandova, A., Kesiova, M., and Todorov, S., In vivo effects of amtolmetin guacyl on lipid peroxidation and antioxidant defence systems. Comparison with non-selective and COX-2 selective NSAIDs. Auton. Autacoid Pharmacol., 27, 99–104 (2007).

    Article  PubMed  CAS  Google Scholar 

  • Lie, H. K. and Turner, S. C., Early experience with the use of celecoxib in a child and adolescent population. J. Pharm. Practice Res., 32, 27–31 (2002).

    Google Scholar 

  • Liu, H., Wei, W., and Li, X., Celecoxib exacerbates hepatic fibrosis and induces hepatocellular necrosis in rats treated with porcine serum. Prostaglandins Other Lipid Mediat., 88, 63–67 (2009).

    Article  PubMed  CAS  Google Scholar 

  • Lu, S., Zhang, X., Badawi, A. F., El-Sohemy, A., and Archer, M. C., Cyclooxygenase-2 inhibitor celecoxib inhibits promotion of mammary tumorigenesis in rats fed a high fat diet rich in n-6 polyunsaturated fatty acids. Cancer Lett., 8, 12 (2002).

    Google Scholar 

  • Meister, A. and Tate, S. S., Glutathione and related gammaglutamyl compounds: biosynthesis and utilization. Annu. Rev. Biochem., 45, 559–604 (1976).

    Article  PubMed  CAS  Google Scholar 

  • Misra, H. P. and Fridovich, I., The role of superoxide anion in the autoxidation of epinephrine and a simple assay for superoxide dismutase. J. Biol. Chem., 25, 3170–3175 (1972).

    Google Scholar 

  • Morales, E. and Mucksavage, J. J., Cyclooxygenase-2 inhibitor-associated acute renal failure: case report with rofecoxib and review of the literature. Pharmacotherapy, 22, 1317–1321 (2002).

    Article  PubMed  Google Scholar 

  • Orhan, H., Doğruer, D. S., Çakir, B., Sahin, G., and Sahin, M. F., The in vitro effects of new non-steroidal antiinflammatory compounds on antioxidant system of human erythrocytes. Exp. Toxicol. Pathol., 51, 397–402 (1999).

    PubMed  CAS  Google Scholar 

  • Ozaki, N. K., Beharry, K. D., Nishihara, K. C., Akmal, Y., Ang, J. G., and Abrantes, M., Comparative effects of dexamethasone and celecoxib on growth in newborn rabbits exposed to hyperoxia/normoxia. Suppl. Pediatr. Res., 49, 298A (2001).

    Google Scholar 

  • Ozaki, N., Beharry, K., Kenji, C., Nishihara, K. C., Akmal, Y., Ang, J. G., Abrantes, M., and Modanlou, H. D., Differential regulation of prostacyclin and thromboxane by dexamethasone and celecoxib during oxidative stress in newborn rabbits. Prostaglandins Other Lipid Mediat., 70, 61–78 (2002).

    Article  PubMed  CAS  Google Scholar 

  • Ozgocmen, S., Ardicoglu, O., Erdogan, H., Fadillioglu, E., and Gudul, H., In vivo effect of celecoxib and tenoxicam on oxidant/anti-oxidant status of patients with knee osteoarthritis. Ann. Clin. Lab. Sci., 35, 137–143 (2005).

    PubMed  CAS  Google Scholar 

  • Papaioannides, D., Bouropoulos, C., Sinapides, D., Korantzopoulos, P., and Akritidis, N., Acute renal dysfunction associated with selective COX-2 inhibitor therapy. Int. Urol. Nephrol., 33, 609–611 (2001).

    Article  PubMed  CAS  Google Scholar 

  • Paulson, S. K., Zhang, J. Y., Breau, A. P., Hribar, J. D., Liu, N. W., Jessen, S. M., Lawal, Y. M., Cogburn, J. N., Gresk, C. J., Markos, C. S., Maziasz, T. J., Schoenhard, G. L., and Burton, E. G., Pharmacokinetics, tissue distribution, metabolism, and excretion of celecoxib in rats. Drug Metab. Dispos., 28, 514–521 (2000).

    PubMed  CAS  Google Scholar 

  • Pleban, P. A., Munyani, A., and Beachum, J., Determination of selenium concentration and glutathione peroxidase activity in plasma and erythrocytes. Clin. Chem., 28, 311–316 (1982).

    PubMed  CAS  Google Scholar 

  • Provost, J. P., Hanton, G., and Le Net, J. L., Plasma triglycerides: an overlooked biomarker of hepatotoxicity in the rat. Comparative Clin. Pathol., 12, 95–101 (2003).

    Article  CAS  Google Scholar 

  • Rosai, J., Rosai and Ackerman’s Surgical Pathology. Mosby, Philadelphia, pp. 648–711, (2004).

    Google Scholar 

  • Satoh, K., Serum lipid peroxide in cerebrovascular disorders determined by a new colorimetric method. Clin. Chim. Acta, 90, 37–43 (1978).

    Article  PubMed  CAS  Google Scholar 

  • Sheth, N., Essentials for starting a pediatric clinical study (4): Clinical pediatric safety planning based on preclinical toxicity studies and pediatric pharmacovigilance guidance. J. Toxicol. Sci., 34Suppl 2, SP327–SP329 (2009).

    Article  PubMed  Google Scholar 

  • Stempak, D., Gammon, J., Klein, J., Koren, G., and Baruchel, S., Single-dose and steady-state pharmacokinetics of celecoxib in children. Clin. Pharmacol. Ther., 72, 490–497, (2002).

    Article  PubMed  CAS  Google Scholar 

  • Stempak, D., Gammon, J., Halton, J., Moghrabi, A., Koren, G., and Baruchel, S., A pilot pharmacokinetic and antiangiogenic biomarker study of celecoxib and low-dose metronomic vinblastine or cyclophosphamide in pediatric recurrent solid tumors. J. Pediatr. Hematol. Oncol., 28, 720–728 (2006).

    Article  PubMed  CAS  Google Scholar 

  • Tan, H. H., Ong, W. M., Lai, S. H., and Chow, W. C., Nimesulide-induced hepatotoxicity and fatal hepatic failure. Singapore Med. J., 48, 582–585 (2007).

    PubMed  CAS  Google Scholar 

  • Tanaka, A., Hase, S., Miyazawa, T., and Takeuchi, K., Up-regulation of cyclooxygenase-1: a key to nonsteroidal anti-inflammatory drug-induced intestinal damage. J. Pharmacol. Exp. Ther., 300, 754–761 (2002).

    Article  PubMed  CAS  Google Scholar 

  • Tietz, N. W., Biochemical Aspects of Hematology. Fundamentals of Clinical Chemistry. W.B. Saunders Co., Philadelphia, pp. 803–805, (1987).

    Google Scholar 

  • Turner, S. and Ford, V., Role of the selective cyclo-oxygenase-2 (COX-2) inhibitors in children. Arch. Dis. Child Educ. Pract. Ed., 89, ep46–ep49 (2004).

    Article  Google Scholar 

  • Vane, J. R., Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat. New Biol., 23, 232–235 (1971).

    Google Scholar 

  • Vane, J. R., Mitchell, J. A., Appleton, I., Tomlinson, A., Bishop-Bailey, D., Croxtall, J., and Willoughby, D. A., Inducible isoforms of cyclooxygenase and nitric-oxide synthase in inflammation. Proc. Natl. Acad Sci. U. S. A., 15, 2046–2050 (1994).

    Article  Google Scholar 

  • Wallace, J. L., The 1994 Merck Frosst. Award. Mechanisms of nonsteroidal anti-inflammatory drug (NSAID) induced gastrointestinal damage-potential for development of gastrointestinal tract safe NSAIDs. Can. J. Physiol. Pharmacol., 72, 1493–1498 (1994).

    PubMed  CAS  Google Scholar 

  • Yagi, K., Assay for blood plasma or serum. Methods Enzymol., 105, 328–331 (1984).

    Article  PubMed  CAS  Google Scholar 

  • Yan, B., Leung, Y., Urbanski, S. J., and Myers, R. P., Rofecoxib-induced hepatotoxicity: a forgotten complication of the coxibs. Can. J. Gastroenterol., 20, 351–355 (2006).

    PubMed  Google Scholar 

  • Zhang, M. Z., Wang, J. L., Cheng, H. F., Harris, R. C., and McKanna, J. A., Cyclooxygenase-2 in rat nephron development. Am. J. Physiol., 273, F994–F1002 (1997).

    PubMed  CAS  Google Scholar 

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Correspondence to Ferzan Lermioglu.

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Sozer, S., Diniz, G. & Lermioglu, F. Effects of celecoxib in young rats: Histopathological changes in tissues and alterations of oxidative stress/antioxidant defense system. Arch. Pharm. Res. 34, 253–259 (2011). https://doi.org/10.1007/s12272-011-0211-3

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