Abstract
Cyclophosphamide (CP) causes extensive cystitis, which is ameliorated with concomitant treatment with mesna. We investigated the protective mechanisms of mesna in the expression of uroplakin (UP), a strong mucosal barrier against toxic materials, in CP-induced rat cystitis. A total of 54 SD female rats received a single intraperitoneal injection of 200 mg of CP/kg. Six CP-treated, 6 CP + mesna (120 mg/kg)-treated rats, and 6 negative controls were sequentially sacrificed at 12, 24, and 72 h post-CP injection. The bladders were harvested. The levels of UPIa, Ib, II, and III mRNA on real-time PCR, the UPII and III expressions on immunoblotting, and the UPII expression on immunolocalization study in the harvested bladder were maximally suppressed within 12–24 h, whereas partially or completely recovered at 24–72 h post-CP injection. In addition, the responses in UPs after a CP insult were heterogeneous (i.e., markedly suppressed in UPII and lesser destructive in UPIII). Even though the mesna-treated rats also showed transient and small reductions in the mRNA levels of all UPs, mesna clearly preserved the UP expressions of mRNA and protein in CP-induced urinary bladder mucosa. In conclusion, this study suggests that CP transiently reduces the expression of UPs and mesna protects the urinary bladder mucosa through the preservation of UPs protein.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Al-Rawithi S, El-Yazigi A, Ernst P, Al-Fiar F, Nicholls PJ (1998) Urinary excretion and pharmacokinetics of acrolein and its parent drug cyclophosphamide in bone marrow transplant patients. Bone Marrow Transplant 22:485–490
Batista CK, Brito GA, Souza ML, Leitão BT, Cunha FQ, Ribeiro RA (2006) A model of hemorrhagic cystitis induced with acrolein in mice. Braz J Med Biol Res 39:1475–1481
Byun Y, Park HY, Kim H, Lee G (2008) Differences in Chlamydia trachomatis cryptic plasmid loads in two types of female commercial sex workers in Korea. Jpn J Infect Dis 61:146–147
Choi SH, Byun Y, Lee G (2009) Expressions of uroplakins in the mouse urinary bladder with cyclophosphamide-induced cystitis. J Korean Med Sci 24:684–689
Elias A, Ryan L, Sulkes A, Collins J, Aisner J, Antman KH (1989) Response to mesna, doxorubicin, ifosfamide, and dacarbazine in 108 patients with metastatic or unresectable sarcoma and no prior chemotherapy. J Clin Oncol 7:1208–1216
Hornberger J, Reyes C, Lubeck D, Valente N (2008) Economic evaluation of rituximab plus cyclophosphamide, vincristine and prednisolone for advanced follicular lymphoma. Leuk Lymphoma 49:227–236
Hu P, Deng FM, Liang FX, Hu CM, Auerbach AB, Shapiro E, Wu XR, Kachar B, Sun TT (2000) Ablation of uroplakin III gene results in small urothelial plaques, urothelial leakage, and vesicoureteral reflux. J Cell Biol 151:961–972
James CA, Mant TG, Rogers HJ (1987) Pharmacokinetics of intravenous and oral sodium 2-mercaptoethane sulphonate (mesna) in normal subjects. Br J Clin Pharmacol 23:561–568
Kanat O, Kurt E, Yalcinkaya U, Evrensel T, Manavoglu O (2006) Comparison of uroprotective efficacy of mesna and amifostine in cyclophosphamide-induced hemorrhagic cystitis in rats. Indian J Cancer 43:12–15
Katz A, Epelman S, Anelli A, Gorender EF, Cruz SM, Oliveira RM, Marques LA (1995) A prospective randomized evaluation of three schedules of mesna administration in patients receiving an ifosfamide-containing chemotherapy regimen: sustained efficiency and simplified administration. J Cancer Res Clin Oncol 121:128–131
Levine LA, Richie JP (1989) Urological complications of cyclophosphamide. J Urol 141:1063–1069
Negrete HO, Lavelle JP, Berg J, Lewis SA, Zeidel ML (1996) Permeability properties of the intact mammalian bladder epithelium. Am J Physiol 271(4 Pt 2):F886–F894
Olioso D, Boaretti M, Ligozzi M, Lo Cascio G, Fontana R (2007) Detection and quantification of hepatitis B virus DNA by SYBR green real-time polymerase chain reaction. Eur J Clin Microbiol Infect Dis 26:43–50
Ormstad K, Orrenius S, Låstbom T, Uehara N, Pohl J, Stekar J, Brock N (1983) Pharmacokinetics and metabolism of sodium 2-mercaptoethanesulfonate in the rat. Cancer Res 43:333–338
Romih R, Veranic P, Jezernik K (2002) Appraisal of differentiation markers in urothelial cells. Appl Immunohistochem Mol Morphol 10:339–343
Santos GW, Tutschka PJ, Brookmeyer R, Saral R, Beschorner WE, Bias WB, Braine HG, Burns WH, Elfenbein GJ, Kaizer H et al (1983) Marrow transplantation for acute nonlymphocytic leukemia after treatment with busulfan and cyclophosphamide. N Engl J Med 309:1347–1353
Takamoto S, Sakura N, Namera A, Yashiki M (2004) Monitoring of urinary acrolein concentration in patients receiving cyclophosphamide and ifosphamide. J Chromatogr B Analyt Technol Biomed Life Sci 806:59–63
West NJ (1997) Prevention and treatment of hemorrhagic cystitis. Pharmacotherapy 17:696–706
Wu XR, Manabe M, Yu J, Sun TT (1990) Large scale purification and immunolocalization of bovine uroplakins I, II, and III. Molecular markers of urothelial differentiation. J Biol Chem 265:19170–19179
Wu XR, Medina JJ, Sun TT (1995) Selective interactions of UPIa and UPIb, two members of the transmembrane 4 superfamily, with distinct single transmembrane-domained proteins in differentiated urothelial cells. J Biol Chem 270:29752–29759
Acknowledgments
The present research was supported by the Research Fund of Dankook University in 2009.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Kyung, Y.S., Park, H.Y. & Lee, G. Preservation of uroplakins by 2-mercaptoethanesulfonate in cyclophosphamide-induced rat cystitis. Arch Toxicol 85, 51–57 (2011). https://doi.org/10.1007/s00204-010-0523-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00204-010-0523-y