Skip to main content
PMC home page
Cancer Science logoLink to Cancer Science
. 2005 Aug 19;94(11):948–952. doi: 10.1111/j.1349-7006.2003.tb01383.x

Enhancement of urinary bladder carcinogenesis by combined treatment with benzyl isothiocyanate and N‐butyl‐N‐(4‐hydroxybutyl)nitrosamine in rats after initiation

Kazushi Okazaki 1,2, Takashi Umemura 1, Takayoshi Imazawa 1, Akiyoshi Nishikawa 1, Toshiaki Masegi 3, Masao Hirose 1,✉
PMCID: PMC11160183  PMID: 14611670

Abstract

Previously we reported that benzyl isothiocyanate (BITC) strongly enhanced rat urinary bladder carcinogenesis after initiation with N‐butyl‐N‐(4‐hydroxybutyl)nitrosamine (BBN), while potently inhibiting BBN‐induction of lesions when given simultaneously with the carcinogen. In the present experiment, the effects of simultaneous treatment with BITC and low‐dose BBN on the postinitiation period of rat urinary bladder carcinogenesis were examined. After treatment with 500 ppm BBN for 4 weeks for initiation, groups of 20, 6‐week‐old, F344 male rats were given 25 ppm BBN alone, basal diet alone, or 100 or 1000 ppm BITC in the diet together with or without 25 ppm BBN in their drinking water for 36 weeks and then killed for autopsy. Further groups consisting of 10 rats each were similarly given BITC or the basal diet together with or without 25 ppm BBN, without initiation treatment. In the initiated groups receiving subsequent BBN exposure, papillary and nodular hyperplasia, dysplasia and carcinoma incidences were significantly increased, and they were further increased by the combined treatment with 100 and 1000 ppm BITC in a dosedependent manner. In the non‐initiation groups, carcinomas were only observed in a single rat in each of the BBN‐treated control and BBN/BITC 100 ppm treatment groups. The results indicate that simultaneous treatment with BITC and a low dose of BBN does not inhibit, but rather enhances rat urinary bladder carcinogenesis after appropriate initiation, and further suggest that BITC may be a human risk factor, at least in high‐risk populations.

References

  • 1. Vineis P, Esteve J, Hartge P, Hoover R, Silverman DT, Terracini B. Effects of timing and type of tobacco in cigarette‐induced bladder cancer. Cancer Res 1988; 48: 3849–52. [PubMed] [Google Scholar]
  • 2. Clavel J, Cordier S, Boccon‐Gibod L, Hemon D. Tobacco and bladder cancer in males: increased risk for inhalers and smokers of black tobacco. Int J Cancer 1989; 44: 605–10. [DOI] [PubMed] [Google Scholar]
  • 3. Radomski JL. The primary aromatic amines: their biological properties and structure‐activity relationships. Annu Rev Pharmacol Toxicol 1979; 19: 129–57. [DOI] [PubMed] [Google Scholar]
  • 4. Malaveille C, Vineis P, Esteve J, Ohshima H, Brun G, Hautefeuille A, Gallet P, Ronco G, Terracini B, Bartsch H. Levels of mutagens in the urine smokers of black and blond tobacco correlate with their risk of bladder cancer. Carcinogenesis 1989; 10: 577–86. [DOI] [PubMed] [Google Scholar]
  • 5. Bartsch H, Caporaso N, Coda M, Kadlubar F, Malaveille C, Skipper P, Talaska G, Tannenbaum SR, Vineis P. Carcinogen hemoglobin adducts, urinary mutagenicity, and metabolic phenotype in active and passive cigarette smokers. J Natl Cancer Inst 1990; 82: 1826–31. [DOI] [PubMed] [Google Scholar]
  • 6. Yamasaki E, Ames BN. Concentration of mutagens from urine by absorption with the nonpolar resin XAD‐2: cigarette smokers have mutagenic urine. Proc Natl Acad Sci USA 1977; 74: 3555–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7. Burchardt M, Burchardt T, Shabsigh A, Taille ADL, Benson MC, Sawczuk I. Current concepts in biomarker technology for bladder cancers. Clin Chem 2000; 46: 595–605. [PubMed] [Google Scholar]
  • 8. VanEtten CH, Daxenbichler ME, Williams PH, Kwolek WF. Glucosinolates and derived products in cruciferous vegetables. Analysis of the edible part from twenty‐two varieties of cabbage. J Agric Food Chem 1976; 24: 452–5. [DOI] [PubMed] [Google Scholar]
  • 9. Carlson DG, Daxenbichler ME, VanEtten CH, Tookey HL, Williams PH. Glucosinolates in crucifer vegetables: turnips and rutabagas. J Agric Food Chem 1981; 29: 1235–9. [DOI] [PubMed] [Google Scholar]
  • 10. Hecht SS. Inhibition of carcinogenesis by isothiocyanates. Drug Metab Rev 2000; 32: 395–411. [DOI] [PubMed] [Google Scholar]
  • 11. Zhang Y, Talalay P. Anticarcinogenic activities of organic isothiocyanates: chemistry and mechanisms. Cancer Res (Suppl) 1994; 54: 1976–81. [PubMed] [Google Scholar]
  • 12. Chung F‐L, Conaway CC, Rao CV, Reddy BS. Chemoprevention of colonic aberrant crypt foci in Fischer rats by sulforaphane and phenethyl isothiocyanate. Carcinogenesis 2000; 21: 2287–91. [DOI] [PubMed] [Google Scholar]
  • 13. Wilkinson JT, Morse MA, Kresty LA, Stoner GD. Effect of alkyl chain length on inhibition of N‐nitrosomethylbenzylamine‐induced esophageal tumorigenesis and DNA methylation by isothiocyanates. Carcinogenesis 1995; 16: 1011–5. [DOI] [PubMed] [Google Scholar]
  • 14. Stoner GD, Adams C, Kresty LA, Amin SG, Desai D, Hecht SS, Murphy SE, Morse MA. Inhibition of N'‐nitrosonornicotine‐induced esophageal tumorigenesis by 3‐phenylpropyl isothiocyanate. Carcinogenesis 1998; 19: 2139–43. [DOI] [PubMed] [Google Scholar]
  • 15. Morse MA, Eklind KI, Hecht SS, Jordan KG, Choi C‐I, Desai DH, Amin SG, Chung F‐L. Structure‐activity relationships for inhibition of 4‐(methylnitrosamino)‐1‐(3‐pyridyl)‐1‐butanone lung tumorigenesis by arylalkyl isothiocyanates in A/J mice. Cancer Res 1991; 51: 1846–50. [PubMed] [Google Scholar]
  • 16. Lin J‐M, Amin S, Trushin N, Hecht SS. Effects of isothiocyanates on tumorigenesis by benzo[a]pyrene in murine tumor models. Cancer Lett 1993; 74: 151–9. [DOI] [PubMed] [Google Scholar]
  • 17. Wattenberg LW. Inhibition of carcinogenic effects of polycyclic hydrocarbons by benzyl isothiocyanate and related compounds. J Natl Cancer Inst 1977; 58: 395–8. [DOI] [PubMed] [Google Scholar]
  • 18. Nishikawa A, Furukawa F, Uneyama C, Ikezaki S, Tanakamaru Z, Chung F‐L, Takahashi M, Hayashi Y. Chemopreventive effects of phenethyl isothiocyanate on lung and pancreatic tumorigenesis in N‐nitrosobis(2‐oxopropyl)amine‐treated hamsters. Carcinogenesis 1996; 17: 1381–4. [DOI] [PubMed] [Google Scholar]
  • 19. Goosen TC, Mills DE, Hollenberg PF. Effects of benzyl isothiocyanate on rat and human cytochromes p450: identification of metabolites formed by p450 2B1. J Pharmacol Exp Ther 2001; 296: 198–206. [PubMed] [Google Scholar]
  • 20. Thapliyal R, Maru GB. Inhibition of cytochrome p450 isozymes by curcumins in vitro and in vivo . Food Chem Toxicol 2001; 39: 541–7. [DOI] [PubMed] [Google Scholar]
  • 21. Conaway CC, Jiao D, Chung F‐L. Inhibition of rat liver cytochrome p450 isozymes by isothiocyanates and their conjugates: a structure‐activity relationship study. Carcinogenesis 1996; 17: 2423–7. [DOI] [PubMed] [Google Scholar]
  • 22. Zhang Y, Talalay P. Mechanism of differential potencies of isothiocyanates as inducers of anticarcinogenic phase 2 enzymes. Cancer Res 1998; 58: 4632–9. [PubMed] [Google Scholar]
  • 23. Hecht SS, Chung F‐L, Richie JP Jr, Akerkar SA, Borukhova A, Skowronski L, Carmella SG. Effects of watercress consumption on metabolism of tobacco‐specific lung carcinogen in smokers. Cancer Epidemiol Biomarkers Prev 1995; 4: 877–84. [PubMed] [Google Scholar]
  • 24. Hecht SS. Chemoprevention of cancer by isothiocyanates, modifiers of carcinogen metabolism. J Nutr 1999; 129: 768–74. [DOI] [PubMed] [Google Scholar]
  • 25. Spitz MR, Duphorne CM, Detry MA, Pillow PC, Amos CI, Lei L, de Andrade M, Gu X, Hong WK, Wu X. Dietary intake of isothiocyanates: evidence of a joint effect with glutathione S‐transferase polymorphisms in lung cancer risk. Cancer Epidemiol Biomarkers Prev 2000; 9: 1017–20. [PubMed] [Google Scholar]
  • 26. Zhao B, Seow A, Lee EJD, Poh WT, The M, Eng P, Wang Y‐T, Tan W‐C, Yu MC, Lee H‐P. Dietary isothiocyanates, glutathione S‐transferase‐M1, ‐T1 polymorphisms and lung cancer risk among Chinese woman in Singapore. Cancer Epidemiol Biomarkers Prev 2001; 10: 1063–7. [PubMed] [Google Scholar]
  • 27. Okazaki K, Yamagishi M, Son H‐Y, Imazawa T, Furukawa F, Nakamura H, Nishikawa A, Masegi T, Hirose M. Simultaneous treatment with benzyl isothiocyanate, a strong bladder promoter, inhibits rat urinary bladder carcinogenesis by N‐butyl‐N‐(4‐hydroxybutyl)nitrosamine. Nutr Cancer 2002; 42: 211–6. [DOI] [PubMed] [Google Scholar]
  • 28. Hirose M, Yamaguchi T, Kimoto N, Ogawa K, Futakuchi M, Sano M, Shirai T. Strong promoting activity of phenylethyl isothiocyanate and benzyl isothiocyanate on urinary bladder carcinogenesis in F344 male rats. Int J Cancer 1998; 77: 773–7. [DOI] [PubMed] [Google Scholar]
  • 29. Ogawa K, Futakuchi M, Hirose M, Boonyaphiphat P, Mizoguchi Y, Miki T, Shirai T. Stage and organ dependent effects of 1‐O‐hexyl‐2,3,5‐trimethylhy‐droquinone, ascorbic acid derivatives, N‐heptadecane‐8,10‐dione and phenylethyl isothiocyanate in a rat multiorgan carcinogenesis model. Int J Cancer 1998, 76: 851–6. [DOI] [PubMed] [Google Scholar]
  • 30. Ogawa K, Hirose M, Cui L, Sugiura S, Cui L, Imaida K, Ogiso T, Shirai T. Dose dependent effect of phenylethyl isothiocyanate in the rat urinary bladder and liver carcinogenesis. Nutr Cancer 2001; 40: 134–9. [DOI] [PubMed] [Google Scholar]
  • 31. Bruggeman IM, Temmink JHM, Van Bladeren. Glutathione‐ and cysteinemediated cytotoxicity of allyl isothiocyanate. Toxicol Appl Pharmacol 1986; 83: 349–59. [DOI] [PubMed] [Google Scholar]
  • 32. Getahun SM, Chung F‐L. Conversion of glucosinolates to isothiocyanates in humans after ingestion of cooked watercress. Cancer Epidemiol Biomarkers Prev 1999; 8: 447–51. [PubMed] [Google Scholar]
  • 33. Masutomi N, Toyoda K, Shibutani M, Niho N, Uneyama C, Takahashi N, Hirose M. Toxic effects of benzyl and allyl isothiocyanates and benzyl‐isoform specific metabolites in the urinary bladder after a single intravesical application to rats. Toxicol Pathol 2001; 29: 617–22. [DOI] [PubMed] [Google Scholar]
  • 34. Akagi K, Sano M, Goshima H, Ogawa K, Hirose M, Shirai T. The involvement of toxic response as an early event in the carcinogenic process of urinary bladder by phenethyl isothiocyanate (PEITC), benzyl isothiocyanaye (BITC) and their analogues in F344 rats. Toxicol Pathol 2003; in press. [DOI] [PubMed]
  • 35. Nakazima M, Yoshida R, Shimada N, Yamazaki H, Yokoi T. Inhibition and inactivation of human cytochrome p450 isoforms by phenethyl isothiocyanate. Drug Metab Dispos 2001; 29: 1110–3. [PubMed] [Google Scholar]
  • 36. Chung F‐L, Morse MA, Eklind KI, Lewis J. Quantitation of human uptake of the anticarcinogen phenethyl isothiocyanate after a watercress meal. Cancer Epidemiol Biomarkers Prev 1992; 1: 383–8. [PubMed] [Google Scholar]
  • 37. Sones K, Heaney RK, Fenwick GR. An estimate of the mean daily intake of glcosinolates from cruciferous vegetables in the UK. J Sci Food Agric 1984; 35: 712–20. [Google Scholar]
  • 38. Kassie F, Pool‐Zobel B, Parzefall W, Knasmuller S. Genotoxic effects of benzyl isothiocyanate, a natural chemopreventive agent. Mutagenesis 1999; 14: 595–604. [DOI] [PubMed] [Google Scholar]
  • 39. Yamaguchi T. Mutagenicity of isothiocyanates, thiocyanates and thioureas on Salmonella typhimurium . Agric Biol Chem 1980; 44: 3017–8. [Google Scholar]
  • 40. Musk SRR, Johnson IT. The clastogenic effects of isothiocyanates. Mutat Res 1993; 300: 111–7. [DOI] [PubMed] [Google Scholar]
  • 41. Sugiura S, Ogawa K, Hirose M, Takeshita F, Asamoto M, Shirai T. Reversibility of proliferative lesions and induction of non‐papillary tumors in rat urinary bladder treated with phenylethyl isothiocyanate. Carcinogenesis 2003; 24: 547–53. [DOI] [PubMed] [Google Scholar]
  • 42. Wakai K, Takashi M, Okamura K, Yuba H, Suzuki K, Murase T, Obata K, Itoh H, Kato T, Kobayashi M, Sakata T, Otani T, Ohshima S, Ohno Y. Foods and nutrients in relation to bladder cancer risk: a case‐control study in Aichi Prefecture, Central Japan. Nutr Cancer 2000; 38: 13–22. [DOI] [PubMed] [Google Scholar]
  • 43. Dunnick JK, Prejean JD, Haseman J, Thompson, RB , Giles HD, McConnel EE. Carcinogenesis bioassay of allyl isothiocyanate. Fundam Appl Toxicol 1982; 2: 114–20. [DOI] [PubMed] [Google Scholar]

Articles from Cancer Science are provided here courtesy of Wiley

RESOURCES