Skip to main content
Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 1990 May;81(5):483–488. doi: 10.1111/j.1349-7006.1990.tb02595.x

Urothelial Damage and Tumor Initiation by Urinary Metabolites of Sodium o‐Phenylphenate in the Urinary Bladder of Female Rats

Ryohei Hasegawa 1,, Fumio Furukawa 1, Kazuhiro Toyoda 1, Hidetaka Sato 1, Michihito Takahashi 1, Yuzo Hayashi 1
PMCID: PMC5918068  PMID: 2116397

Abstract

Intravesical instillation of 2‐phenyl‐1,4‐benzoquinone (PBQ), a metabolite of sodium o‐phenylphenate (Na‐OPP), at a concentration of 0.1% in saline caused acute epithelial injury, prolonged inflammation and epithelial hyperplasia in female F344 rats. Ten such instillations of PBQ within 5 weeks resulted in the development of preneoplastic lesions of the urinary bladder epithelium when followed by 5% sodium saccharin feeding for 31 weeks. Since neither urothelial damage nor tumor‐initiating activity was observed with either Na‐OPP itself or another metabolite, phenylhydroquinone, PBQ may play an essential role in Na‐OPP urinary bladder carcinogenesis.

Keywords: Sodium o‐phenylphenate; 2‐Phenyl‐1,4‐benzoquinone; Urinary bladder carcinogenesis; Tumor initiation; Female rat

Full Text

The Full Text of this article is available as a PDF (412.6 KB).

REFERENCES

  • 1. ) Shirasu , Y. , Moriya , M. , Kato , K. , Tezuka , H. , Henmi , R. , Shingu , A. , Kaneda , M. and Teramoto , S.Mutagenisity testing on o‐phenylphenol . Mutat. Res. , 54 , 227 ( 1978. ). [Google Scholar]
  • 2. ) Kawachi , T. , Yahagi , T. , Kada , T. , Tazima , Y. , Ishidate , M. , Sasaki , M. and Sugiyama , T.Cooperative programme on short‐term assays for carcinogenicity in Japan . In “ Molecular and Cellular Aspects of Carcinogen Scanning Tests ,” ed. Montesano R. , Bartsch H. , Tomatis L. and Davis W. , IARC Sci. Publications; , No. 27, pp. 323 – 330 ( 1980. ). IARC; , Lyon . [PubMed] [Google Scholar]
  • 3. ) Reitz , R. H. , Fox , T. R. , Quast , J. F. , Hermann , E. A. and Watanabe , P. G.Biochemical factors involved in the effects of orthophenylphenol (OPP) and sodium ortho‐phenylphenate (SOPP) on the urinary tract of male F344 rats . Toxicol. Appl. Pharmacol. , 73 , 345 – 349 ( 1984. ). [DOI] [PubMed] [Google Scholar]
  • 4. ) Tayama‐Nawai , S. , Yoshida , S. , Nakao , T. and Hiraga , K.Induction of chromosome aberrations and sister‐chromatid exchanges in CHO‐K1 by o‐phenylphenol . Mutat. Res. , 141 , 95 – 99 ( 1984. ). [DOI] [PubMed] [Google Scholar]
  • 5. ) Suzuki , H. , Suzuki , N. , Sasaki , M. and Hiraga , K.Orthophenylphenol mutagenicity in a human cell strain . Mutat. Res. , 156 , 123 – 127 ( 1985. ). [DOI] [PubMed] [Google Scholar]
  • 6. ) Hiraga , T. and Fujii , T.Induction of tumours of the urinary system in F344 rats by dietary administration of sodium o‐phenylphenate . Food Chem. Toxicol. , 19 , 303 – 310 ( 1981. ). [DOI] [PubMed] [Google Scholar]
  • 7. ) Hiraga , K. and Fujii , T.Induction of tumors of the urinary bladder in F344 rats by dietary administration of o‐phenylphenol . Food Chem. Toxicol. , 22 , 865 – 870 ( 1984. ). [DOI] [PubMed] [Google Scholar]
  • 8. ) Fukushima , S. , Kurata , Y. , Ogiso , T. , Okuda , M. , Miyata , Y. and Ito , N.Pathological analysis of the carcinogenicity of sodium o‐phenylphenate and o‐phenylphenol . Oncology , 42 , 304 – 311 ( 1985. ). [DOI] [PubMed] [Google Scholar]
  • 9. ) Fukushima , S. , Kurata , Y. , Shibata , M. , Ikawa , E. and Ito , N.Promoting effect of sodium o‐phenylphenate and o‐phenylphenol on two‐stage urinary bladder carcinogenesis in rats . Gann , 74 , 625 – 632 ( 1983. ). [PubMed] [Google Scholar]
  • 10. ) Hagiwara , A. , Shibata , M. , Hirose , M. , Fukushima , S. and Ito , N.Long‐term toxicity and carcinogenicity study of sodium o‐phenylphenate in B6C3F1 mice . Food Chem. Toxicol. , 22 , 809 – 814 ( 1984. ). [DOI] [PubMed] [Google Scholar]
  • 11. ) Hasegawa , R. , Takahashi , S. , Asamoto , M. , Shirai , T. and Fukushima , S.Species differences in sodium o‐phenylphenate induction of urinary bladder lesions . Cancer Lett. , in press . [DOI] [PubMed]
  • 12. ) Furuta , K. , Sato , H. , Furukawa , F. , Takahashi , M. , Hasegawa , R. and Hayashi , Y.Dose‐response study on urinary bladder carcinogenesis induced with sodium o‐phenylphenate in F344 rats . Proc. Jpn. Cancer Assoc. 47th Annu. Meet. , 102 ( 1988. ). [Google Scholar]
  • 13. ) Reitz , R. H. , Fox , T. R. , Quast , J. F. , Hermann , E. A. and Watanabe , P. G.Molecular mechanisms involved in the toxicity of orthophenylphenol and its sodium salt . Chem. Biol. Interact. , 43 , 99 – 119 ( 1983. ). [DOI] [PubMed] [Google Scholar]
  • 14. ) Nakao , T. , Ushiyama , K. , Kabashima , J. , Nagai , F. , Nakagawa , A. , Ohno , T. , Ichikawa , H. , Kobayashi , H. and Hiraga , K.The metabolic profile of sodium o‐phenylphenate after subchronic oral administration to rats . Food Chem. Toxicol. , 21 , 325 – 329 ( 1983. ). [DOI] [PubMed] [Google Scholar]
  • 15. ) Sato , M. , Tanaka , A. , Tsuchiya , T. , Yamaha , T. , Nakaura , S. and Tanaka , S.Excretion, distribution and metabolic fate of sodium o‐phenylphenate and o‐phenylphenol in the rat . J. Food Hyg. Soc. , 29 , 7 – 12 ( 1988. ). [Google Scholar]
  • 16. ) Morimoto , K. , Fukuoka , M. , Hasegawa , R. , Tanaka , A. , Takahashi , A. and Hayashi , Y.DNA damage in urinary bladder epithelium of male F344 rats treated with 2‐phenyl‐1,4‐benzoquinone, one of the non‐conjugated urinary metabolites of sodium o‐phenylphenate . Jpn. J. Cancer Res. , 78 , 1027 – 1030 ( 1987. ). [PubMed] [Google Scholar]
  • 17. ) Morimoto , K. , Sato , M. , Fukuoka , M. , Hasegawa , R. , Takahashi , T. , Tsuchiya , T. , Tanaka , A. , Takahashi , A. and Hayashi , Y.Correlation between the DNA damage in urinary bladder epithelium and the urinary 2‐phenyl‐1,4‐benzoquinone levels from F344 rats fed sodium o‐phenylphenate in the diet . Carcinogenesis , 10 , 1823 – 1827 ( 1989. ). [DOI] [PubMed] [Google Scholar]
  • 18. ) Fujii , T. , Nakamura , K. and Hiraga , K.Effects of pH on the carcinogenicity of o‐phenylphenol and sodium o‐phenylphenate in the rat urinary bladder . Food Chem. Toxicol. , 25 , 359 – 362 ( 1987. ). [DOI] [PubMed] [Google Scholar]
  • 19. ) Fukushima , S. , Inoue , T. , Uwagawa , S. , Shibata , M‐A. and Ito , N.Co‐carcinogenic effects of NaHCO3 on o‐phenyl‐phenol‐induced rat bladder carcinogenesis . Carcinogenesis , 10 , 1635 – 1640 ( 1989. ). [DOI] [PubMed] [Google Scholar]
  • 20. ) Teuber , H. J. and Rau , W.Reaktionen mit Nitrosodisulfonat. II. Mitteilung: Uber die Bildung von Chinonen aus einwertigen Phenolen . Chem. Ber. , 86 , 1036 – 1047 ( 1953. ). [Google Scholar]
  • 21. ) Ohtani , M. , Fukushima , S. , Okamura , T. , Sakata , T. , Ito , N. , Koike , K. and Niijima , T.Effects of intravesical instillation of antitumor chemotherapeutic agents on bladder carcinogenesis in rats treated with N‐butyl‐N‐(4‐hydroxybutyl)nitrosamine . Cancer , 54 , 1525 – 1529 ( 1984. ). [DOI] [PubMed] [Google Scholar]
  • 22. ) Fukushima , S. , Hirose , M. , Tsuda , H. , Shirai , T. , Hirao , K. , Arai , M. and Ito , N.Histological classification of urinary bladder cancers in rats induced by N‐butyl‐N‐(4‐hydroxybutyl)nitrosamine . Gann , 67 , 81 – 90 ( 1976. ). [PubMed] [Google Scholar]
  • 23. ) Ito , N. , Shirai , T. and Miyata , Y.Production of urinary bladder tumors by administration of N‐butyl‐N‐(4‐hydroxybutyl)nitrosamine (BBN) to pregnant, nursing and newborn rats . In “ Tumours of Early Life in Man and Animals ,” ed. Severi L. , pp. 495 – 503 ( 1978. ). Monteluce; , Perugia . [Google Scholar]
  • 24. ) Nakanishi , K. , Hagiwara , A. , Shibata , M. , Imaida , K. , Tatematsu , M. and Ito , N.Dose response of saccharin in induction of urinary bladder hyperplasia in Fischer 344 rats pretreated with N‐butyl‐N‐(4‐hydroxybutyl)nitrosamine . J. Natl. Cancer Inst. , 65 , 1005 – 1010 ( 1980. ). [PubMed] [Google Scholar]
  • 25. ) Anderstrom , C. and Johansson , S. L.The combined effect of mechanical trauma and phenacetin or sodium saccharin on the rat urinary bladder . Acta Pathol. Immunol. Scand. Sect. A , 91 , 381 – 389 ( 1983. ). [DOI] [PubMed] [Google Scholar]
  • 26. ) Hasegawa , R. , Furukawa , F. , Toyoda , K. , Sato , H. , Shimoji , N. , Takahashi , M. and Hayashi , Y.In situ freezing of the urinary bladder: a trigger of rapid development of sodium o‐phenylphenate‐induced urinary bladder tumors in the rat . Carcinogenesis , 10 , 571 – 575 ( 1989. ). [DOI] [PubMed] [Google Scholar]
  • 27. ) Reitz , R. H. and Watanabe , P. G.Importance of non‐genotoxic mechanisms in carcinogenesis . In “ Development in the Science and Practice of Toxicology ,” ed. Hayes A. W. , Schnell R. C. and Miya T. S. , pp. 163 – 172 ( 1983. ). Elsevier Science Publishers; , Amsterdam . [Google Scholar]
  • 28. ) Fukushima , S. , Shibata , M. , Shirai , T. , Tamano , S. and Ito , N.Roles of urinary sodium ion concentration and pH in promotion by ascorbic acid of urinary bladder carcinogenesis in rats . Cancer Res. , 46 , 1623 – 1626 ( 1986. ). [PubMed] [Google Scholar]
  • 29. ) Hasegawa , R. and Cohen , S. M.The effects of different salts of saccharin on the rat urinary bladder . Cancer Lett. , 30 , 261 – 268 ( 1986. ). [DOI] [PubMed] [Google Scholar]
  • 30. ) Hasegawa , R. , Shimoji , N. , Furukawa , F. , Fukuoka , M. , Kasai , H. , Takahashi , M. and Hayashi , Y.Effects of intravesical instillation of OPP‐Na metabolites in the rat urinary bladder carcinogenesis . Proc. Japanese Cancer Assoc., 47th Annu. Meet. , 9 , ( 1988. ). [Google Scholar]
  • 31. ) Grisham , J. W. , Kaufmann , W. K. and Kaufman , D. G.The cell cycle and chemical carcinogenesis . Surv. Synth. Pathol. Res. , 1 , 49 – 66 ( 1983. ). [Google Scholar]
  • 32. ) Grasso , P.Persistent organ damage and cancer production in rats and mice . Arch. Toxicol. Suppl. , 11 , 75 – 83 ( 1987. ). [DOI] [PubMed] [Google Scholar]
  • 33. ) Shirai , T. , Tagawa , Y. , Fukushima , S. , Imaida , K. and Ito , N.Strong promoting activity of reversible uracil‐induced urolithiasis on urinary bladder carcinogenesis in rats initiated with N‐butyl‐N‐(4‐hydroxybutyl)‐nitrosamine . Cancer Res. , 47 , 6726 – 6730 ( 1988. ). [PubMed] [Google Scholar]
  • 34. ) Greenfield , R. E. , Ellwein , L. B. and Cohen , S. M.A general probabilistic model of carcinogenesis: analysis of experimental urinary bladder carcinogenesis . Carcinogenesis , 5 , 437 – 445 ( 1984. ). [DOI] [PubMed] [Google Scholar]

Articles from Japanese Journal of Cancer Research : Gann are provided here courtesy of Wiley

RESOURCES