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Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 1988 Apr;79(4):460–465. doi: 10.1111/j.1349-7006.1988.tb01614.x

Effects of Phenobarbital and Carbazole on Carcinogenesis of the Lung, Thyroid, Kidney, and Bladder of Rats Pretreated with N‐Bis(2‐hydroxypropyl)nitrosamine

Tomoyuki Shirai 1,✉, Atsuko Masuda 1, Katsumi Imaida 1, Tadashi Ogiso 1, Nobuyuki Ito 1
PMCID: PMC5917507  PMID: 3133336

Abstract

Studies were made on potential modifying effects of phenobarbital (PB) and carbazole on tumor development induced by N‐bis(2‐hydroxypropyl)nitrosamine (DHPN), a wide‐spectrum carcinogen in rats. Effects on the lung, thyroid, kidney, bladder and liver were investigated. Male F344 rats were given 0.2% DHPN in their drinking water for 1 week and then 0.05% PB or 0.6% carbazole in their diet for 50 weeks. Control animals were treated with either DHPN or PB or carbazole only. Neither PB nor carbazole affected the incidence or histology of lung tumors. However, PB promoted the development of thyroid tumors and preneoplastic lesions of the liver, while carbazole promoted the induction of renal pelvic tumors.

Keywords: Phenobarbital, Carbazole, N‐Bis(2‐hydroxypropyl)nitrosamine, Carcinogenesis, Rat

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References

  • 1. ) Peraino , C. , Fry , R. J. M. and Staffeldt , E.Reduction and enhancement by phenobarbital of hepatocarcinogenesis induced in the rat by 2‐acetylaminofluorene . Cancer Res. , 31 , 1506 – 1512 ( 1971. ). [PubMed] [Google Scholar]
  • 2. ) Hirose , M. , Shirai , T. , Tsuda , H. , Fukushima , S. , Ogiso , T. and Ito , N.Effect of phenobarbital, polychlorinated biphenyl and sodium saccharin on hepatic and renal carcinogenesis in unilaterally nephrectomized rats given N‐ethyl‐N‐hydroxyethyl‐nitrosamine orally . Carcinogenesis , 2 , 1299 – 1302 ( 1981. ). [DOI] [PubMed] [Google Scholar]
  • 3. ) Kitagawa , T. and Sugano , H.Enhancing effect of phenobarbital on the development of enzyme‐altered islands and hepatocellular carcinomas initiated by 3′‐methyl‐4‐(dimethylamino)azobenzene or diethylnitrosamine . Gann , 69 , 679 – 687 ( 1978. ). [PubMed] [Google Scholar]
  • 4. ) Ward , J. M.Increased susceptibility of livers of aged F344/NCr rats to the effects of phenobarbital on the incidence, morphology, and histochemistry of hepatocellular foci and neoplasms . J. Natl. Cancer Inst. , 71 , 815 – 823 ( 1983. ). [PubMed] [Google Scholar]
  • 5. ) International Agency for Research on Cancer Phenobarbital and phenobarbital sodium . In“Some Miscellaneous Pharmaceutical Substances,” IARC Monograph on Evaluation of the Carcinogenic Risk of Chemicals in Man , Vol. 13 , pp. 157 – 181 ( 1977. ). IARC; , Lyon . [Google Scholar]
  • 6. ) Tsuda , H. , Fukushima , S. , Imaida , K. , Kurata , Y. and Ito , N.Organ‐specific promoting effect of phenobarbital and saccharin in induction of thyroid, liver and urinary bladder tumors in rats after initiation with N‐nitrosomethylurea . Cancer Res. , 43 , 3292 – 3296 ( 1983. ). [PubMed] [Google Scholar]
  • 7. ) Hiasa , Y. , Kitahori , Y. , Konishi , N. , Enoki , N. and Fujita , T.Effect of varying the duration of exposure to phenobarbital on its enhancement of N‐bis(2‐hydroxypropyl)‐nitrosamine induced thyroid tumorigenesis in male Wistar rats . Carcinogenesis , 4 , 935 – 937 ( 1983. ). [DOI] [PubMed] [Google Scholar]
  • 8. ) Shirai , T. , Lee , M.‐S. , Wang , Y. C. and King , C. M.Effects of partial hepatectomy and dietary phenobarbital on liver and mammary tumorigenesis by two N‐hydroxy‐N‐acylaminobiphenyls in female CD rats . Cancer Res. , 41 , 2450 – 2456 ( 1981. ). [PubMed] [Google Scholar]
  • 9. ) Naito , M. , Aoyama , H. and Ito , A.Inhibitory effect of phenobarbital on the development of gliomas in WF rats treated neonatally with N‐ethyl‐N‐nitrosourea . J. Natl. Cancer Inst. , 74 , 725 – 728 ( 1985. ). [PubMed] [Google Scholar]
  • 10. ) Friedman , G. D.Barbiturates and lung cancer in humans . J. Natl. Cancer Inst. , 67 , 291 – 295 ( 1981. ). [PubMed] [Google Scholar]
  • 11. ) Pnonmarkow , V. and Tomatis , L.The effect of long‐term administration of phenobarbitone in DF‐1 mice . Cancer Lett. , 1 , 165 – 172 ( 1976. ). [Google Scholar]
  • 12. ) Uchida , E. and Hirono , I.Effect of phenobarbital on induction of liver and lung tumors by dimethylnitrosamine in newborn mice . Gann , 70 , 639 – 644 ( 1979. ). [PubMed] [Google Scholar]
  • 13. ) Tsuchiya , E. , Concetti , H. F. , Sugano , H. and Kitagawa , T.Lack of promoting effect of phenobarbital on pulmonary tumorigenesis in ddy mice initiated by transplacental exposure to l‐ethyl‐l‐nitrosourea . Gann , 75 , 305 – 310 ( 1984. ). [PubMed] [Google Scholar]
  • 14. ) Pereira , M. A. , Knutsen , G. L. and Herren‐Freund , S. L.Effect of subsequent treatment of chloroform or phenobarbital on the incidence of liver and lung tumors initiated by ethylnitrosourea in 15 day old mice . Carcinogenesis , 6 , 203 – 207 ( 1985. ). [DOI] [PubMed] [Google Scholar]
  • 15. ) Hoffmann , D. , Rathkamp , G. and Woziwodzki , H.Chemical studies on tobacco smoke. VI. The determination of carbazoles in cigarette smoke . Beitr. Tabakforsch. , 4 , 253 – 263 ( 1968. ). [Google Scholar]
  • 16. ) Tsuda , H. , Hagiwara , A. , Shibata , M. , Ohshima , M. and Ito , N.Carcinogenic effect of carbazole in the liver of (C57BL/6N × C3H/HeN)F1 mice . J. Natl. Cancer Inst. , 69 , 1383 – 1389 ( 1982. ). [PubMed] [Google Scholar]
  • 17. ) Van Duuren , B. L. , Bilbao , J. A. and Joseph , C. A.The carcinogenic nitrogen heterocyclics in cigarette‐smoke condensate . J. Natl. Cancer Inst. , 25 , 53 – 61 ( 1960. ). [PubMed] [Google Scholar]
  • 18. ) Boyland , E. and Brues , A. M.Carcinogenic action of dibenzcarbazoles . Proc. R. Soc. London, Ser. B , 122 , 429 – 441 ( 1937. ). [Google Scholar]
  • 19. ) Lacassagne , A. , Buu‐Hoi , N. P. , Zajdela , F. , Perin , F. and Jacquignon , P.Nature of potent carcinogens: benzopyridocarbazoles . Nature , 191 , 1005 – 1006 ( 1961. ). [Google Scholar]
  • 20. ) Sellakumar , A. , Stenbäck , F. , Rowland , J. and Shubik , P.Tumor induction by 7H‐dibenzo(c,g)carbazole in the respiratory tract of Syrian hamsters . J. Toxicol. Environ. Health , 3 , 935 – 939 ( 1977. ). [DOI] [PubMed] [Google Scholar]
  • 21. ) Shirai , T. , Kurata , Y. , Fukushima , S. and Ito , N.Dose‐related induction of lung, thyroid and kidney tumors by N‐bis(2‐hydroxypropyl)nitrosamine given orally to F344 rats . Gann , 75 , 502 – 507 ( 1984. ). [PubMed] [Google Scholar]
  • 22. ) Shirai , T. , Masuda , A. , Hirose , M. , Ikawa , E. and Ito , N.Enhancement of N‐bis‐(2‐hydroxypropyl)nitrosamine‐initiated lung tumor development in rats by bleomycin and N‐methyl‐N‐nitrosourethane . Cancer Lett. , 25 , 25 – 31 ( 1984. ). [DOI] [PubMed] [Google Scholar]
  • 23. ) Mohr , U. , Reznik , G. and Pour , P.Carcinogenic effects of diisopropanolnitrosamines in Sprague‐Dawley rats . J. Natl. Cancer Inst. , 58 , 361 – 366 ( 1977. ). [DOI] [PubMed] [Google Scholar]
  • 24. ) Shirai , T. , Tsuda , H. , Ogiso , T. , Hirose , M. and Ito , N.Organ specific modifying potential of ethinyl estradiol on carcinogenesis initiated with different carcinogens . Carcinogenesis , 8 , 115 – 119 ( 1987. ). [DOI] [PubMed] [Google Scholar]
  • 25. ) Hiasa , Y. , Kitahori , Y. , Ohshima , M. , Fujita , T. , Yuasa , T. , Konishi , N. and Miyasiro , A.Promoting effects of phenobarbital and barbital on development of thyroid tumors in rats treated with N‐bis(2‐hydroxypropyl)‐nitrosamine . Carcinogenesis , 3 , 1187 – 1190 ( 1982. ). [DOI] [PubMed] [Google Scholar]
  • 26. ) Gelboin , H. V.Cancer susceptibility and carcinogen metabolism . N. Engl. J. Med. , 297 , 384 – 386 ( 1977. ). [DOI] [PubMed] [Google Scholar]
  • 27. ) Niebert , D. W. and Gelboin , H. V.The in vivo and in vitro induction of aryl hydrocarbon hydroxylase in mammalian cells of different species, tissues, strains and developmental and hormonal states . Arch. Biochem. Biophys. , 134 , 76 – 89 ( 1969. ). [DOI] [PubMed] [Google Scholar]
  • 28. ) Hiasa , Y. , Kitahori , Y. , Konishi , N. , Shimoyama , T. and Lin , J.‐C.Sex differential and dose dependence of phenobarbital‐promoting activity in N‐bis(2‐hydroxy‐propyl)nitrosamine‐initiated thyroid tumorigenesis in rats . Cancer Res. , 45 , 4087 – 4090 ( 1985. ). [PubMed] [Google Scholar]
  • 29. ) Ito , N. , Fukushima , S. , Shirai , T. and Nakanishi , K.Effects of promoters on N‐butyl‐N‐(4‐hydroxybutyl) nitrosamineinduced urinary bladder carcinogenesis in the rat . Environ. Health Perspect. , 50 , 61 – 69 ( 1983. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30. ) Diwan , B. A. , Palmer , A. E. , Oshima , M. and Rice , J. M.N‐Nitroso‐N‐methylurea initiation in multiple tissues for organspecific tumor promotion in rats by phenobarbital . J. Natl. Cancer Inst. , 75 , 1099 – 1105 ( 1985. ). [PubMed] [Google Scholar]
  • 31. ) Imaida , K. , Fukushima , S. , Shirai , T. , Masui , T. , Ogiso , T. and Ito , N.Promoting activities of butylated hydroxyanisole, butylated hydroxytoluene and sodium L‐ascorbate on forestomach and urinary bladder carcinogenesis initiated with methylnitrosourea in F344 male rats . Gann , 75 , 769 – 775 ( 1984. ). [PubMed] [Google Scholar]
  • 32. ) Fukushima , S. , Sakata , T. , Tagawa , Y. , Shibata , M. , Hirose , M. and Ito , N.Different modifying response of butylated hydroxyanisole, butylated hydroxytoluene, and other antioxidants in N,N‐dibutylnitrosamine esophagus and forestomach carcinogenesis of rats . Cancer Res. , 47 , 2113 – 2116 ( 1987. ). [PubMed] [Google Scholar]

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