Carcinogenicity and Modification of Carcinogenic Response by Antioxidants

  • Nobuyuki Ito
  • Masao Hirose
  • Akihiro Hagiwara
  • Satoru Takahashi
Part of the Basic Life Sciences book series (BLSC, volume 52)

Abstract

Synthetic or naturally occurring antioxidants such as butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate sodium L-ascorbate, and α-tocopherol have been widely used as food additives in various processed foods to prevent auto-oxidation of fatty acids. In addition, many naturally occurring antioxidants are present at appreciable levels in plants. In the light of studies which showed that antioxidants lack mutagenic activity and indeed even inhibit mutagenesis induced by carcinogens (13), they have been considered safe for use as food additives. In fact, since they have further been observed to inhibit chemical carcinogenesis in various organs when administered to rats concurrently with carcinogens (5,6,17), they have been considered as anticarcinogenic agents. However, BHA was recently found to be carcinogenic in the rat forestomach (9), and when antioxidants were given to rats after carcinogen exposure, they enhanced carcinogenesis in some organs while exerting an inhibitory influence in others (5–8). Therefore, antioxidants have both hazardous and nonhazardous effects in rodents, and by analogy also possibly in man.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Hirose, M., T. Inoue, M. Asamoto, Y. Tagawa, and N. Ito (1986) 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.PubMedCrossRefGoogle Scholar
  2. 2.
    Hirose, M., A. Masuda, K. Imaida, M. Kagawa, H. Tsuda, and N. Ito (1987) Induction of forestomach lesions in rats by oral administration of naturally occurring antioxidants for 4 weeks. Jpn. J. Cancer Res. (Gann) 78:317–321.Google Scholar
  3. 3.
    Hirose, M., S. Fukushima, Y. Kurata, H. Tsuda, M. Tatematsu, and N. Ito (1988) Modification of N-methyl-N-nitro-N-nitrosoguanidine- induced forestomach and glandular stomach carcinogenesis by phenolic antioxidants in rats. Cancer Res. 48:5310–5315.PubMedGoogle Scholar
  4. 4.
    Hirose, M., M. Asamoto, A. Hagiwara, N. Ito, H. Kaneko, K. Sai to, Y. Takamatsu, A. Yoshitake, and J. Miyamoto (1987) 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.PubMedCrossRefGoogle Scholar
  5. 5.
    Ito, N., and M. Hirose (1987) The role of antioxidants in chemical carcinogenesis. Jpn. J. Cancer Res. (Gann) 78:1011–1026.Google Scholar
  6. 6.
    Ito, N., and M. Hirose (1989) Antioxidants—Carcinogenic and chemopreventive properties. Adv. Cancer Res, (in press).Google Scholar
  7. 7.
    Ito, N., S. Fukushima, and H. Tsuda (1985) Carcinogenicity and modification of the carcinogenic response by BHA, BHT, and other antioxidants. CRC Crit. Rev. Toxicol. 15:109–150.Google Scholar
  8. 8.
    Ito, N., S. Fukushima, and M. Hirose (1987) Modification of the carcinogenic response by antioxidants. In Toxicological Aspects of Foods, K. Miller, ed. Elsevier Applied Science, London and New York, pp. 253–293.Google Scholar
  9. 9.
    Ito, N., S. Fukushima, A. Hagiwara, M. Shibata, and T. Ogiso (1983) Carcinogenicity of butylated hydroxyanisole in F344 rats. J. Natl. Cancer Inst. 70:343–352.PubMedGoogle Scholar
  10. 10.
    Ito, N., S. Fukushima, S. Tamaño, M. Hirose, and A. Hagiwara (1986) Dose-response in butylated hydroxyanisole induction of forestomach carcinogenesis in F344 rats. J. Natl. Cancer Inst. 77:1261–1265.PubMedGoogle Scholar
  11. 11.
    Ito, N., M. Hirose, M. Shibata, T. Shirai, and H. Tanaka (1989) Modifying effects of simultaneous treatment with different doses of butylated hydroxyanisole (BHA) on rat tumor development induced by the wide-spectrum carcinogens 3,2*-dimethyl-4-aminobiphenyl, 2,2*-dihydroxy-di-n-propylnitrosamine or N-methylnitrosourea (submitted for publication).Google Scholar
  12. 12.
    Iverson, F., E. Lok, E. Nera, K. Karpinski, and D.B. Clayson (1985) A 13 week feeding study of butylated hydroxyanisole: The subsquent regression of the induced lesion in male Fischer 344 rat forestomach epithelium. Toxicology 35:1–11.PubMedCrossRefGoogle Scholar
  13. 13.
    Kahl, R. (1984) Synthetic antioxidants: Biochemical action and interference with radiation, toxic compounds, chemical mutagens and chemical carcinogens. Toxicology 33:185–228.PubMedCrossRefGoogle Scholar
  14. 14.
    Masui, T., M. Asamoto, M. Hirose, S. Fukushima, and N. Ito (1987) Regression of simple hyperplasia and papillomas and persistence of basal cell hyperplasia in the forestomach of F344 rats treated with butylated hydroxyanisole. Cancer Res. 47:5171–5174.PubMedGoogle Scholar
  15. 15.
    Masui, T., M. Hirose, K. Imaida, S. Fukushima, S. Tamaño, and N. Ito (1986) Sequential changes of the forestomach of F344 rats, Syrian golden hamsters, and B6C3Fi mice treated with butylated hydroxyanisole. Jpn. J. Cancer Res. (Gann) 77:1083–1090.Google Scholar
  16. 16.
    Saito, K., A. Yoshitake, J. Miyamoto, M. Hirose, and N. Ito (1989) No evidence of DNA adduct formation in forestomach of rats treated with 3-BHA and its metabolites as assessed by an enzymatic 32P- postlabeling method (submitted for publication).Google Scholar
  17. 17.
    Wattenberg, L.W. (1986) Chemoprevention of cancer. Cancer Res. 45:1–8.Google Scholar
  18. 18.
    Yamaguchi, S., M. Hirose, S. Fukushima, R. Hasegawa, and N. Ito (1989) Modification by catechol and resorcinol of upper digestive tract and lung carcinogenesis in rats treated with methyl-n-amylnitrosamine (submitted for publication).Google Scholar

Copyright information

© Plenum Press, New York 1990

Authors and Affiliations

  • Nobuyuki Ito
    • 1
  • Masao Hirose
    • 1
  • Akihiro Hagiwara
    • 1
  • Satoru Takahashi
    • 1
  1. 1.First Department of PathologyNagoya City University Medical SchoolMizuho-cho, Mizuho-ku, Nagoya 467Japan

Personalised recommendations