Skip to main content
PMC home page
Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 1988 Mar;79(3):320–328. doi: 10.1111/j.1349-7006.1988.tb01594.x

Co‐carcinogenic Effect of Retinyl Acetate on Forestomach Carcinogenesis of Male F344 Rats Induced with Butylated Hydroxyanisole

Ryohei Hasegawa 1, Michihito Takahashi 1, Fumio Furukawa 1, Kazuhiro Toyoda 1, Hidetaka Sato 1, Yuzo Hayashi 1
PMCID: PMC5917490  PMID: 3131282

Abstract

The potential modifying effect of retinyl acetate (RA) on butylated hydroxyanisole (BHA)‐induced rat forestomach tumorigenesis was examined. Male F344 rats, 5 weeks of age, were maintained on diet containing 1% or 2% BHA by weight and simultaneously on drinking water supplemented with RA at various concentrations (w/v) for 52 weeks. In groups given 2% BHA, although marked hyperplastic changes of the forestomach epithelium were observed in all animals, co‐administration of 0.25% RA significantly (P<0.05) increased the incidence of forestomach tumors (squamous cell papilloma and carcinoma) to 60% (9/15, 2 rats with carcinoma) from 15% (3/20, one rat with carcinoma) in the group given RA‐free water. In rats given 1% BHA, RA co‐administered at a dose of 0.05, 0.1, 0.2 or 0.25% showed a dose‐dependent enhancing effect on the development of the BHA‐induced epithelial hyperplasia. Tumors, all papillomas, were induced in 3 rats (17%) with 0.25% RA and in one rat (10%) with 0.05% RA co‐administration. RA alone did not induce hyperplastic changes in the forestomach. These findings indicate that RA acted as a co‐carcinogen in the BHA forestomach carcinogenesis of the rat.

Keywords: Butylated hydroxyanisole, Retinyl acetate, Co‐carcinogenicity, Forestomach, Rat

Full Text

The Full Text of this article is available as a PDF (644.2 KB).

References

  • 1. ) Kahl , R.Synthetic antioxidants: biochemical actions and interference with radiation, toxic compounds, chemical mutagens and chemical carcinogens . Toxicology , 33 , 185 – 228 ( 1984. ). [DOI] [PubMed] [Google Scholar]
  • 2. ) Wattenberg , L. W.Chemoprevention of cancer . Cancer Res. , 45 , 1 – 8 ( 1985. ). [PubMed] [Google Scholar]
  • 3. ) Ito , N. , Fukushima , S. , Hagiwara , A. , Shibata , M. and Ogiso , T.Carcinogenicity of butylated hydroxyanisole in F344 rats. J. Natl . Cancer Inst. , 70 , 343 – 352 ( 1983. ). [PubMed] [Google Scholar]
  • 4. ) Ito , N. , Fukushima , S. , Imaida , K. , Sakata , T. and Masui , T.Induction of papilloma in the forestomach of hamsters by butylated hydroxyanisole . Gann , 74 , 459 – 461 ( 1983. ). [PubMed] [Google Scholar]
  • 5. ) Ito , N. , Fukushima , S. and Tsuda , H.Carcinogenicity and modification of the carcinogenic response by BHA, BHT, and other antioxidanls . CRC Crit. Rev. Toxicol. , 15 , 109 – 150 ( 1985. ). [DOI] [PubMed] [Google Scholar]
  • 6. ) Ito , N. , Hirose , M. , Fukushima , S. , Tsuda , H. , Shirai , T. and Tatematsu , M.Studies on antioxidants: their carcinogenic and modifying effects on chemical carcinogenesis . Food Chem. Toxicol. , 24 , 1071 – 1082 ( 1986. ). [DOI] [PubMed] [Google Scholar]
  • 7. ) Chung , F.‐L. , Wang , M. , Carmella , S. G. and Hecht , S. S.Effects of butylated hydroxyanisole on the tumorigenicity and metabolism of N‐nitrosodimethylamine and N‐nitrosopyrrolidine in A/J mice . Cancer Res. , 46 , 165 – 168 ( 1986. ). [PubMed] [Google Scholar]
  • 8. ) Sporn , M. B. and Roberts , A. B.Role of retinoids in differentiation and carcinogenesis . J. Natl. Cancer Inst. , 73 , 1381 – 1387 ( 1984. ). [PubMed] [Google Scholar]
  • 9. ) Lotan , R.Effects of vitamin A and its analogs (retinoids) on normal and neoplastic cells . Biochim. Biophys. Acta , 605 , 33 – 91 ( 1980. ). [DOI] [PubMed] [Google Scholar]
  • 10. ) Muto , Y. and Moriwaki , H.Antitumor activity of vitamin A and its derivatives . J. Natl. Cancer Inst. , 73 , 1389 – 1393 ( 1984. ). [PubMed] [Google Scholar]
  • 11. ) Moon , R. C. and Itri , L. M.Retinoids and cancer . In “ The Retinoids ,” Vol. 2 , ed. Sporn M. B. , Roberts A. B. and Goodman D. S. , pp. 327 – 371 ( 1984. ). Academic Press; , Orlando , FL . [Google Scholar]
  • 12. ) Lupulescu , A.Inhibition of DNA synthesis and neoplastic cell growth by vitamin A (retinol) . J. Natl. Cancer Inst. , 77 , 149 – 156 ( 1986. ). [PubMed] [Google Scholar]
  • 13. ) Huang , C. C.Retinol (vitamin A) inhibition of dimethylnitrosamine (DMN) and diethylnitrosamine (DEN) induced sister‐chromatid exchanges in V79 cells and mutations in Salmonella/microsome assays . Mutat. Res. , 187 , 133 – 140 ( 1987. ). [DOI] [PubMed] [Google Scholar]
  • 14. ) McCormick , D. L. , Burns , F. J. and Albert , R. E.Inhibition of benzo(a)pyrene‐induced mammary carcinogenesis by retinyl acetate . J. Natl. Cancer Inst. , 66 , 559 – 564 ( 1981. ). [PubMed] [Google Scholar]
  • 15. ) Thompson , H. J. , Herbst , E. J. and Meeker , L. D.Chemoprevention of mammay carcinogenesis: a comparative review of the efficacy of a polyamine antimetabolite, retinoids, and selenium . J. Natl. Cancer Inst. , 77 , 595 – 598 ( 1986. ). [DOI] [PubMed] [Google Scholar]
  • 16. ) Murasaki , G. , Miyata , Y. , Babaya , K. , Arai , M. , Fukushima , S. and Ito , N.Inhibitory effect of an aromatic retinoic acid analog on urinary bladder carcinogenesis in rats treated with N ‐ butyl ‐ N ‐ (4 ‐ hydroxybutyl) nitrosamine . Gann , 71 , 333 – 340 ( 1980. ). [PubMed] [Google Scholar]
  • 17. ) Moon , R. C. , McCormick , D. L. and Mehta , R. G.Retinoids as chemopreventive agents: alone and in combination . In “ Vitamins and Cancer: Human Cancer Prevention by Vitamins and Micronutrients ,” ed. Meyskens F. L. and Prasad K. N. , pp. 161 – 180 ( 1985. ). Humana Press; , Clifton , NJ . [Google Scholar]
  • 18. ) Verma , A. K.The differential effects of retinoic acid and 7,8‐benzoflavone on the induction of mouse skin tumors by the initiation‐promotion protocol and by the complete carcinogenesis process . In “ Carcinogenesis ,” Vol. 7 , ed. Hecker E. , pp. 35 – 39 ( 1982. ). Raven Press; , New York . [PubMed] [Google Scholar]
  • 19. ) Kulesz‐Martin , M. , Blumenson , L. , and Lisafeld , B.Retinoic acid enhancement of an early step in the transformation of mouse epidermal cells in vitro . Carcinogenesis , 7 , 1425 – 1429 ( 1986. ). [DOI] [PubMed] [Google Scholar]
  • 20. ) Stinson , S. F. , Reznic , G. and Donahoe , R.Effect of three retinoids on tracheal carcinogenesis with N‐methyl‐N‐nitrosourea in hamsters . J. Natl. Cancer Inst. , 66 , 947 – 951 ( 1981. ). [PubMed] [Google Scholar]
  • 21. ) Quander , R. V. , Leary , S. L. , Strandberg , J. D. , Yarbrough , B. A. and Squire , R. A.Long term effect of 2‐hydroxyethyl retinamide on urinary bladder carcinogenesis and tumor transplantation in Fischer 344 rats . Cancer Res. , 45 , 5235 – 5239 ( 1985. ). [PubMed] [Google Scholar]
  • 22. ) Heshmat , M. Y. , Kaul , L. , Kovi , J. , Jackson , M. A. , Jackson , A. F. , Jones , G. W. , Edson , M. , Enterline , J. P. , Worrell , R. G. and Perry , S. L.Nutrition and prostate cancer: a case‐control study . Prostate , 6 , 7 – 17 ( 1985. ). [DOI] [PubMed] [Google Scholar]
  • 23. ) Kolonel , L. N. , Hankin , J. H. and Yoshizawa , C. N.Vitamin A and prostate cancer in elderly man: enhancement of risk . Cancer Res. , 47 , 2982 – 2985 ( 1987. ). [PubMed] [Google Scholar]
  • 24. ) Underwood , B. A.Vitamin A in animal and human nutrition . In “ The Retinoids ,” Vol. 1 , ed. Sporn M. B. , Roberts A. B. and Goodman D. S. , pp. 281 – 392 ( 1984. ). Academic Press; , Orlando , FL . [Google Scholar]
  • 25. ) Ohno , Y. , Takamura , N. , Kurokawa , Y. and Hayashi , Y.Subacute toxicity studies of retinol acetate in rats . Iyakuhin Kenkyu , 12 , 1064 – 1081 ( 1981. ) ( in Japanese ). [Google Scholar]
  • 26. ) Hirose , M. , Asamoto , M. , Hagiwara , A. and Ito , N.Metabolism of 2‐ and 3‐tert‐butyl‐4‐hydroxyanisole (2‐ and 3‐BHA) in the rat (II): metabolism in forestomach and covalent binding to tissue macromolecules . Toxicology , 45 , 13 – 24 ( 1987. ). [DOI] [PubMed] [Google Scholar]
  • 27. ) Sato , H. , Takahashi , M. , Furukawa , F. , Miyakawa , Y. , Hasegawa , R. , Toyoda , K. and Hayashi , Y.Initiating potential of 2‐(2‐furyl)‐3‐(5‐nitro‐2‐furyl)acrylamide (AF‐2), butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT) and 3,3′,4′,5,7‐pentahydroxyflavone (quercetin) in twostage mouse carcinogenesis . Cancer Lett. , 38 , 49 – 59 ( 1987. ). [DOI] [PubMed] [Google Scholar]
  • 28. ) Kroes , R. and Wester , P. W.Forestomach carcinogenesis: possible mechanisms of action . Food Chem. Toxicol. , 24 , 1083 – 1089 ( 1986. ). [DOI] [PubMed] [Google Scholar]
  • 29. ) Nera , E. A. , Lok , E. , Iverson , F. , Ormsby , E. , Karpinski , K. F. and Clayson , D. B.Short‐term pathological and proliferative effects of butylated hydroxyanisole and other phenolic antioxidants in the forestomach of Fischer 344 rats . Toxicology , 32 , 197 – 213 ( 1984. ). [DOI] [PubMed] [Google Scholar]
  • 30. ) Hirose , M. , Inoue , T. , Asamoto , M. , Tagawa , Y. and Ito , N.Comparison of the effects of 13 phenolic compounds in induction of proliferative lesions of the forestomach and increase in the labelling indices of the glandular stomach and urinary bladder epithelium of Syrian golden hamsters . Carcinogenesis , 7 , 1285 – 1289 ( 1986. ). [DOI] [PubMed] [Google Scholar]
  • 31. ) Giacosa , A. , Stefani , G. and Chiti , D.Epithelial alterations induced by vitamin A deficiency . In “ Nutrition in Gastrointestinal Disease ,” ed. Barbara L. , pp. 13 – 18 ( 1987. ). Raven Press; , New York . [Google Scholar]
  • 32. ) Tanaka , T. , Mori , H. , Fujii , M. , Takahashi , M. and Hirono , I.Carcinogenicity examination of betel quid. II. Effect of vitamin A deficiency on rats fed semipurified diet containing betel nut and calcium hydroxide . Nutr. Cancer , 4 , 260 – 266 ( 1983. ). [DOI] [PubMed] [Google Scholar]
  • 33. ) Chu , E. W. and Malmgren , R. A.An inhibitory effect of vitamin A on the induction of tumors of the forestomach and cervix in the Syrian hamster by carcinogenic polycyclic hydrocarbons . Cancer Res. , 25 , 883 – 895 ( 1965. ). [PubMed] [Google Scholar]
  • 34. ) Smith , D. M. , Rogers , A. E. and Newberne , P. M.Vitamin A and benzo(a)pyrene carcinogenesis in the respiratory tract of hamsters fed a semisynthetic diet . Cancer Res. , 35 , 1485 – 1488 ( 1975. ). [PubMed] [Google Scholar]
  • 35. ) Kurokawa , Y. , Hayashi , Y. , Maekawa , A. , Takahashi , M. and Kokubo , T.High incidences of pheochromocytomas after longterm administration of retinol acetate to F344/DuCrj rats . J. Natl. Cancer Inst. , 74 , 715 – 723 ( 1985. ). [PubMed] [Google Scholar]
  • 36. ) Forbes , P. D. , Urbach , F. and Da Vies , R. E.Enhancement of experimental photocarcinogenesis by topical retinoic acid . Cancer Lett. , 7 , 85 – 90 ( 1979. ). [DOI] [PubMed] [Google Scholar]
  • 37. ) Connor , M. J. , Ashton , R. E. and Lowe , N. J.A comparative study of the induction of epidermal hyperplasia by natural and synthetic retinoids . J Pharmacol. Exp. Ther. , 237 , 31 – 35 ( 1986. ). [PubMed] [Google Scholar]
  • 38. ) Smith , P. M. , Rodgers , A. E. , Herndon , B. J. and Newberne , P. M.Vitamin A (retinyl acetate) and benzo(a)pyrene‐induced respiratory tract carcinogenesis in hamsters fed a commercial diet . Cancer Res. , 35 , 11 – 16 ( 1975. ). [PubMed] [Google Scholar]
  • 39. ) McCormick , D. L. , May , C. M. , Thomas , C. F. and Detrisac , C. J.Anticarcinogenic and hepatotoxic interactions between retinyl acetate and butylated hydroxytoluene in rats . Cancer Res. , 46 , 5264 – 5269 ( 1986. ). [PubMed] [Google Scholar]

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

RESOURCES