Skip to main content
PMC home page
Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 2002 Dec;93(12):1299–1307. doi: 10.1111/j.1349-7006.2002.tb01238.x

Effects of Antioxidant 1‐O‐Hexyl‐2,3,5‐trimethylhydroquinone or Ascorbic Acid on Carcinogenesis Induced by Administration of Aminopyrine and Sodium Nitrite in a Rat Multi‐organ Carcinogenesis Model

Hideaki Yada 1, Masao Hirose 2,✉, Seiko Tamano 3, Mayumi Kawabe 3, Masashi Sano 3, Satoru Takahashi 1, Mitsuru Futakuchi 1, Tokutaro Miki 4, Tomoyuki Shirai 1
PMCID: PMC5926933  PMID: 12495469

Abstract

The effect of antioxidant, 0.25% 1‐O‐hexyl‐2,3,5‐trimethylhydroquinone (HTHQ) or 0.25% ascorbic acid (AsA), on Carcinogenesis induced by administration of 0.05% aminopyrine (AP) and 0.05% sodium nitrite (NaNO2), was examined using a rat multi‐organ carcinogenesis model. Groups of twenty F344 male rats were treated sequentially with an initiation regimen of N‐diethylnitrosamine, N‐methyl‐N‐nitrosourea, N‐butyl‐N‐(4‐hydroxybutyl) nitrosamine, N, N′‐dimethylhydrazine and 2,2′‐dihydroxy‐di‐n‐propylnitrosamine during the first 4 weeks, followed by AP+NaNO2, AP+NaNO2+HTHQ, AP+NaNO2+AsA, NaNO2+HTHQ, NaNO2+AsA, each of the individual chemicals alone or basal diet and tap water as a control. All surviving animals were killed at week 28, and major organs were examined histopathologically for development of preneoplastic and neoplastic lesions. In the AP+NaNO2 group, the incidences of hepatocelluar adenomas and hemangiosarcomas were 95% and 35%, respectively. When HTHQ or AsA was simultaneously administered, the incidences decreased to 58% and 11%, or to 80% and 15%, respectively. On the other hand, in the AP+NaNO2 group and the NaNO2‐alone group, when HTHQ, but not AsA, was simultaneously administered, the incidence of carcinomas in the forestomach significantly increased. The results suggest that HTHQ can prevent tumor production induced by AP and NaNO2 more effectively than AsA. On the other hand, an enhancing or possible carcinogenic effect of simultaneous administration of HTHQ and NaNO2 only on the forestomach is suggested, while simultaneous treatment with the same dose of AsA and NaNO2 may not be carcinogenic to the fore‐stomach or other organs.

Keywords: Antioxidants, Aminopyrine, Sodium nitrite, Carcinogenesis, Rat

Full Text

The Full Text of this article is available as a PDF (72.2 KB).

REFERENCES

  • 1. ) Magee , P. N. , Montesano , R. and Preussmann , R.N‐Nitroso compounds and related carcinogens . In “ Chemical Carcinogens ,” ed. Searles C. E. , ACS Monogr. No. 173 , pp. 491 – 625 ( 1976. ). American Chemical Society; , Washington , DC . [Google Scholar]
  • 2. ) Lijinsky , W. , Taylor , H. W. , Snyder , C. and Nettesheim , P.Malignant tumours of liver and lung in rats fed aminopyrine or heptamethyleneimine together with nitrite . Nature , 244 , 176 – 178 ( 1973. ). [DOI] [PubMed] [Google Scholar]
  • 3. ) Chan , W. C. and Fong , Y. Y.Ascorbic acid prevents liver tumour production by aminopyrine and nitrite in the rat . Int. J. Cancer , 20 , 268 – 270 ( 1977. ). [DOI] [PubMed] [Google Scholar]
  • 4. ) Kawanishi , T. , Ohno , Y. , Takahashi , A. , Ishiwata , H. , Tanimura , A. , Kasuya , Y. and Omori , Y.Studies on nitro‐samine formation by the interaction between drugs and nitrite. I. Measurement of the amount of nitrosamine formed in rat and guinea pig stomachs . J. Toxicol. Sci. , 6 , 261 – 270 ( 1981. ). [DOI] [PubMed] [Google Scholar]
  • 5. ) Kuenzig , W. , Chau , J. , Norkus , E. , Holowaschenko , H. , Newmark , H. , Mergens , W. and Conney , A. H.Caffeic and ferulic acid as blockers of nitrosamine formation . Carcinogenesis , 5 , 309 – 313 ( 1984. ). [DOI] [PubMed] [Google Scholar]
  • 6. ) Li , Y. and Liu , H.Prevention of tumour production in rats fed aminopyrine plus nitrite by sea buckthorn juice . IARC Sci. Publ. , 105 , 568 – 570 ( 1991. ). [PubMed] [Google Scholar]
  • 7. ) Lijinsky , W. and Greenblatt , M.Carcinogen dimethylnitrosamine produced in vivo from nitrite and aminopyrine . Nat. New. Biol. , 236 , 177 – 178 ( 1972. ). [DOI] [PubMed] [Google Scholar]
  • 8. ) Scheunig , G. , Horn , K. H. and Mehnert , W. H.Induction of tumors in Wistar rats after oral application of aminopyrine and nitrite . Arch. Geschwulstforsch. , 49 , 220 – 228 ( 1979. ). [PubMed] [Google Scholar]
  • 9. ) Stich , H. F.Teas and tea components as inhibitors of carcinogen formation in model systems and man . Prev. Med. , 21 , 377 – 384 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 10. ) Ohshima , H. , Friesen , M. , Malaveille , C. , Brouet , I. , Hautefeuille , A. and Bartsch , H.Formation of direct‐acting genotoxic substances in nitrosated smoked fish and meat products: identification of simple phenolic precursors and phenyldiazonium ions as reactive products . Food Chem. Toxicol. , 27 , 193 – 203 ( 1989. ). [DOI] [PubMed] [Google Scholar]
  • 11. ) Lin , J. K. and Lee , S. F.Enhancement of the mutagenicity of polyphenols by chlorination and nitrosation in Salmonella typhimurium . Mutat. Res. , 269 , 217 – 224 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 12. ) Kawabe , M. , Takaba , K. , Yoshida , Y. and Hirose , M.Effects of combined treatment with phenolic compounds and sodium nitrite on two‐stage carcinogenesis and cell proliferation in the rat stomach . Jpn. J. Cancer Res. , 85 , 17 – 25 ( 1994. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13. ) Hirose , M. , Tanaka , H. , Takahashi , S. , Futakuchi , M. , Fukushima , S. and Ito , N.Effects of sodium nitrite and catechol, 3‐methoxycatechol, or butylated hydroxyanisole in combination in a rat multiorgan carcinogenesis model . Cancer Res. , 53 , 32 – 37 ( 1993. ). [PubMed] [Google Scholar]
  • 14. ) Hirose , M. , Fukushima , S. , Hasegawa , R. , Kato , T. , Tanaka , H. and Ito , N.Effects of sodium nitrite and catechol or 3‐methoxycatechol in combination on rat stomach epithelium . Jpn. J. Cancer Res. , 81 , 857 – 861 ( 1990. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15. ) Yoshida , Y. , Hirose , M. , Takaba , K. , Kimura , J. and Ito , N.Induction and promotion of forestomach tumors by sodium nitrite in combination with ascorbic acid or sodium ascorbate in rats with or without N‐methyl‐N'‐nitro‐N‐nitro‐soguanidine pre‐treatment . Int. J. Cancer , 56 , 124 – 128 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 16. ) Hino , T. , Kawanishi , S. , Yasui , H. , Oka , S. and Sakurai , H.HTHQ (1‐O‐hexyl–2,3,5‐trimethylhydroquinone), an antilipid‐peroxidative compound: its chemical and biochemical characterizations . Biochim. Biophys. Acta , 1425 , 47 – 60 ( 1998. ). [DOI] [PubMed] [Google Scholar]
  • 17. ) Hirose , M. , Iwata , S. , Ito , E. , Nihro , Y. , Takahashi , S. , Mizoguchi , Y. , Miki , T. , Satoh , T. , Ito , N. and Shirai , T.Strong anti‐mutagenic activity of the novel lipophilic anti‐ oxidant 1‐O‐hexyl‐2,3,5‐trimethylhydroquinone against heterocyclic amine‐induced mutagenesis in the Ames assay and its effect on metabolic activation of 2‐amino‐6‐methyl‐dipyrido[1,2‐a:3′,2′‐d]imidazole (Glu‐p‐1) . Carcinogenesis , 16 , 2227 – 2232 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 18. ) Hirose , M. , Hasegawa , R. , Kimura , J. , Akagi , K. , Yoshida , Y. , Tanaka , H. , Miki , T. , Satoh , T. , Wakabayashi , K. , Ito , N. and Shirai , T.Inhibitory effects of 1‐O‐hexyl‐2,3,5‐tri‐methylhydroquinone (HTHQ), green tea catechins and other antioxidants on 2‐amino‐6‐methyldipyrido[1,2‐a:3′,2′‐d]‐imidazole (Glu‐P‐1)‐induced rat hepatocarcinogenesis and dose‐dependent inhibition by HTHQ of lesion induction by Glu‐P‐1 or 2‐amino‐3,8‐dimethylimidazo[4,5‐f]quinoxaline (MeIQx) . Carcinogenesis , 16 , 3049 – 3055 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 19. ) Hirose , M. , Akagi , K. , Hasegawa , R. , Yaono , M. , Satoh , T. , Hara , Y. , Wakabayashi , K. and Ito , N.Chemoprevention of 2‐amino‐1‐methyl‐6‐phenylimidazo[4,5‐b]pyridine (PhIP)‐induced mammary gland carcinogenesis by antioxidants in F344 female rats . Carcinogenesis , 16 , 217 – 221 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 20. ) Futakuchi , M. , Hirose , M. , Miki , T. , Tanaka , H. , Ozaki , M. and Shirai , T.Inhibition of DMBA‐initiated rat mammary tumour development by 1‐O‐hexyl‐2,3,5‐trimethylhydroquinone, phenylethyl isothiocyanate, and novel synthetic ascorbic acid derivatives . Eur. J. Cancer Prev. , 7 , 153 – 159 ( 1998. ). [PubMed] [Google Scholar]
  • 21. ) Mizoguchi , Y. , Hirose , M. , Yamaguchi , T. , Boonyaphiphat , P. , Miki , T. and Shirai , T.Dose dependence of 1‐O‐hexyl‐2,3,5‐trimethylhydroquinone promotion of forestomach carcinogenesis in rats pretreated with N‐ethylnitrosourethane . Jpn. J. Cancer Res. , 89 , 475 – 480 ( 1998. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22. ) Kamm , J. J. , Dashman , T. , Conney , A. H. and Burns , J. J.Protective effect of ascorbic acid on hepatotoxicity caused by sodium nitrite plus aminopyrine . Proc. Natl. Acad. Sci. USA , 70 , 747 – 749 ( 1973. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23. ) Mirvish , S. S. , Pelfrene , A. F. , Garcia , H. and Shubik , P.Effect of sodium ascorbate on tumor induction in rats treated with morpholine and sodium nitrite, and with nitrosomorpholine . Cancer Lett. , 2 , 101 – 108 ( 1976. ). [DOI] [PubMed] [Google Scholar]
  • 24. ) Sasaki , Y. , Kawaguchi , S. , Kawaguchi , A. , Tsuchimine , S. , Iwama , K. and Tsuda , S.Evaluation of in vivo genotoxicity of nitrosoamines derived from sodium nitrite and secondary amines (abstr.) . J. Toxicol. Sci. , 26 , 234 ( 2001. ). [Google Scholar]
  • 25. ) Scanlan , R. A.Formation and occurrence of nitrosamines in food . Cancer Res. , 43 ( Suppl. ), 2435s – 2440s ( 1983. ). [PubMed] [Google Scholar]
  • 26. ) Kono , Y. , Shibata , H. , Kodama , Y. and Sawa , Y.The suppression of N‐nitrosating reaction by chlorogenic acid . Biochem. J. , 312 , 947 – 953 ( 1995. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27. ) Nihro , Y. , Furukawa , H. , Sogawa , S. , Wang , T. C. , Miyataka , H. , Matsumoto , H. , Miki , T. and Satoh , T.Synthesis and anti lipid‐peroxidation activity of hydroquinone monoalkyl esters . Chem. Pharm. Bull. , 42 , 576 – 579 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 28. ) Inai , K. , Kobuke , T. , Fujihara , M. , Yonehara , S. , Takemoto , T. , Tsuya , T. , Yamamoto , A. , Tachiyama , Y. , Izumi , K. and Tokuoka , S.Lack of tumorigenicity of aminopyrine orally administered to B6C3F1 mice . Jpn. J. Cancer Res. , 81 , 122 – 128 ( 1990. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29. ) Ito , N. , Tsuda , H. , Tatematsu , M. , Inoue , T. , Tagawa , Y. , Aoki , T. , Uwagawa , S. , Kagawa , M. , Ogiso , T. , Masui , T. , Imaida , K. , Fukushima , S. and Asamoto , M.Enhancing effect of various hepatocarcinogens on induction of preneoplastic glutathione S‐transferase placental form positive foci in rats an approach for a new medium‐term bioassay system . Carcinogenesis , 9 , 387 – 394 ( 1988. ). [DOI] [PubMed] [Google Scholar]
  • 30. ) Ogawa , K. , Futakuchi , M. , Hirose , M. , Boonyaphiphat , P. , Mizoguchi , Y. , Miki , T. and Shirai , T.Stage and organ dependent effects of 1–0–hexyl‐2,3,5‐trimethylhydroquinone, ascorbic acid derivatives, n‐heptadecane‐8,10‐dione and phenylethyl isothiocyanate in a rat multiorgan carcinogenesis model . Int. J. Cancer , 76 , 851 – 856 ( 1998. ). [DOI] [PubMed] [Google Scholar]
  • 31. ) Ito , N. , Hirose , M. and Takahashi , S.Cellular proliferation and stomach carcinogenesis induced by antioxidants . In “ Chemically Induced Cell Proliferation: Implications for Risk Assessment ,” ed. Butterworth B. E. , Slaga T. J. , Farland W. and McClain M. , pp. 43 – 52 ( 1991. ). Wiley‐Liss; , New York . [PubMed] [Google Scholar]
  • 32. ) Nakagawa , S. , Kogiso , S. , Yoshitake , A. , Hirose , M. and Ito , N.32P‐Postlabeling analysis of DNA‐adduct formation in the forestomach and glandular stomach of rats treated with catechol or related phenolic compounds (abstr.) . Proc. Jpn. Cancer Assoc. , 48 , 70 ( 1991. ). [Google Scholar]
  • 33. ) Kikugawa , K. and Kato , T.Formation of mutagenic diazoquinone by interaction of phenol with nitrite . Food Chem. Toxicol. , 26 , 209 – 214 ( 1988. ). [DOI] [PubMed] [Google Scholar]
  • 34. ) Block , G.Anti‐oxidant intake in the U.S . Toxicol. Ind. Health , 9 , 295 – 301 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 35. ) Tannenbaum , S. R. , Sinskey , A. J. , Weisman , M. and Bishop , W.Nitrite in human saliva: its possible relationship to nitrosamine formation . J. Natl. Cancer Inst. , 53 , 79 – 84 ( 1974. ). [PubMed] [Google Scholar]
  • 36. ) Granli , T. , Dahl , R. , Brodin , P. and Bockman , O. C.Nitrate and nitrite concentrations in human saliva: variations with salivary flow‐rate . Food Chem. Toxicol. , 27 , 675 – 680 ( 1989. ). [DOI] [PubMed] [Google Scholar]
  • 37. ) Knight , T. M. , Forman , D. , Al‐Dabbagh , S. A. and Doll , R.Estimation of dietary intake of nitrate and nitrite in Great Britain . Food Chem. Toxicol. , 25 , 277 – 285 ( 1987. ). [DOI] [PubMed] [Google Scholar]

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

RESOURCES