Skip to main content
PMC home page
Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 1998 May;89(5):475–480. doi: 10.1111/j.1349-7006.1998.tb03286.x

Dose Dependence of 1‐O‐Hexyl‐2,3,5‐trimethylhydroquinone Promotion of Forestomach Carcinogenesis in Rats Pretreated with N‐Ethylnitrosourethane

Yasumoto Mizoguchi 1, Masao Hirose 1,✉, Tsuyoshi Yamaguchi 1, Plemjit Boonyaphiphat 1,†, Tokutaro Miki 2, Tomoyuki Shirai 1
PMCID: PMC5921845  PMID: 9685849

Abstract

Post‐initiation dose‐dependent effects of the chemopreventive antioxidant 1‐O‐hexyl‐2,3,5‐trimethylhydroquinone (HTHQ), a potent inhibitor of heterocyclic amine‐induced mutagenesis and carcinogenesis, on the development of forestomach and tongue tumors were investigated in male F344 rats. Groups of 22 rats were treated with 0.01% ethylnitrosourethane (ENUR) as an initiator in the drinking water for 4 weeks, then placed on diet containing 1.0%, 0.5%, 0.25% or 0.125% HTHQ, or basal diet alone for 36 weeks. Further groups of 12 rats each were similarly treated with the different doses of HTHQ or given basal diet alone for 36 weeks without prior ENUR treatment. All animals were killed at week 40. Tongue papillary hyperplasia and papillomas tended to be increased in the groups treated with ENUR followed by 0.5–0.125% HTHQ, though there was no effect at the highest dose, in line with increased bromodeoxyuridine labeling indices. In the forestomach, the incidences of papillomas and carcinomas were also significantly elevated only in the group treated with ENUR followed by 0.125% HTHQ. Without ENUR pretreatment, papillary hyperplasia was found in the 1–0.125% HTHQ groups and the labeling index was also increased, though without clear dose dependence. The results indicate that HTHQ may have very weak or weak promotion potential for tongue and forestomach carcinogenesis, but that both minimum and maximum thresholds for active dose levels may exist.

Keywords: Key words, Forestomach carcinogenesis, Antioxidant, Dose‐dependence, Rat

Full Text

The Full Text of this article is available as a PDF (56.3 KB).

REFERENCES

  • 1. ) Nihro , Y. , Furukawa , H. , Sogawa , S. , Wang , T. C. , Miyataka , H. , Natsumoto , H. , Miki , T. and Satoh , T.Synthesis and anti lipid‐peroxidation activity of hydroquinone monoalkyl ethers . Chem. Pharm. Bull. , 42 , 576 – 579 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 2. ) 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]
  • 3. ) 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‐trimethylhydroquinone (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]
  • 4. ) 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]
  • 5. ) Futakuchi , M. , Hirose , M. , Miki , T. , Tanaka , H. , Ozaki , M. and Shirai , T.Inhibition of DMBA‐initiated rat mammary tumor development by the novel synthetic ascorbic acid derivatives, synthetic phenolic antioxidant 1‐O‐hexyl‐2,3,5‐trimethylhydroquinone (HTHQ) and phenylethyl isothiocyanate . Eur. J. Cancer Prev. , 7 ( 1998. ), in press . [PubMed] [Google Scholar]
  • 6. ) Ogawa , K. , Hirose , M. , Futakuchi , M. , Boonyaphiphat , P. , Mizoguchi , Y. , Miki , T. and Shirai , T.Stage and organ dependent effects of 1‐O‐hexyl‐2,3,5‐trimethylhydroquinone, ascorbic acid derivatives and n‐heptadecane‐8,10‐dione, and phenylethyl isothiocyanate in a rat multi‐organ carcinogenesis model . Int. J. Cancer , 73 ( 1998. ), in press . [DOI] [PubMed] [Google Scholar]
  • 7. ) Hirose , M. , Maekawa , A. , Kamiya , S. and Odashima , S.Carcinogenic effect of N‐ethyl‐ and N‐amylnitrosourethanes on female Donryu rats . Gann , 70 , 653 – 662 ( 1979. ). [PubMed] [Google Scholar]
  • 8. ) Maekawa , A. , Onodera , H. , Matsushima , Y. , Nagaoka , T. , Todate , A. , Shibutani , M. , Kodama , Y. and Hayashi , Y.Dose‐response carcinogenicity in rats on low‐dose levels of N‐ethyl‐N‐nitrosourethane . Jpn. J. Cancer Res. , 80 , 632 – 636 ( 1989. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9. ) Hirose , M. , Kagawa , M. , Ogawa , K. , Yamamoto , A. and Ito , N.Antagonistic effect of diethylmaleate on the promotion of forestomach carcinogenesis by butylated hydroxyanisole (BHA) in rats pretreated with N‐methyl‐N'‐nitro‐N‐nitrosoguanidine . Carcinogenesis , 10 , 2223 – 2226 ( 1989. ). [DOI] [PubMed] [Google Scholar]
  • 10. ) Hirose , M. , Yada , H. , Hakoi , K. , Takahashi , S. and Ito , N.Modification of carcinogenesis by α‐tocopherol, t‐butylhydroquinone, propyl gallate and butylated hydroxytoluene in a rat multi‐organ carcinogenesis model . Carcinogenesis , 14 , 2359 – 2364 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 11. ) Hagiwara , A. , Tanaka , H. , Imaida , K. , Tamano , S. , Fukushima , S. and Ito , N.Correlation between medium‐term multi‐organ carcinogenesis bioassay data and long‐term observation results in rats . Jpn. J. Cancer Res. , 84 , 237 – 245 ( 1993. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12. ) Ito , N. , Hirose , M. and Takahashi , S.Cell proliferation and forestomach carcinogenesis. Environ . Health Perspect. , 101 ( Suppl. 5 ), 107 – 110 ( 1993. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13. ) Hirose , M. , Takahashi , S. and Shirai , T.Characteristics of forestomach carcinogenesis by non‐genotoxic phenolic compounds . J. Toxicol. Pathol. , 8 , 277 – 284 ( 1995. ). [Google Scholar]
  • 14. ) Hirose , M. , Fukushima , S. , Kurata , Y. , Tsuda , H. , Tatematsu , M. and Ito , N.Modification of N‐methyl‐N'‐nitro‐N‐nitrosoguanidine‐induced forestomach and glandular stomach carcinogenesis by phenolic antioxidants in rats . Cancer Res. , 48 , 5310 – 5315 ( 1988. ). [PubMed] [Google Scholar]
  • 15. ) Schilderman , P. A. E. L. , van Maanen , J. M. S. , Smeets , E. J. , ten Hoor , F. and Kleinjans , J. C. S.Oxygen radical formation during prostaglandin H synthase‐mediated biotrans‐formation of butylated hydroxyanisole . Carcinogenesis , 14 , 347 – 353 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 16. ) Schilderman , P. A. E. L. , van Maanen , J. M. S. , ten Vaarwerk , F. J. , Lafleur M. V. M. , Westmijze , E. J. , ten Hoor , F. and Kleinjans , J. C. S.The role of prostaglandin H synthase‐mediated metabolism in the induction of oxidative DNA damage by BHA metabolites . Carcinogenesis , 14 , 1297 – 1302 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 17. ) Li , Y. and Trush , M. A.DNA damage resulting from the oxidation of hydroquinone by copper: role for a Cu(II)/Cu(I) redox cycle and reactive oxygen generation . Carcinogenesis , 14 , 1303 – 1311 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 18. ) Hiraku , Y. and Kawanishi , S.Oxidative DNA damage and apoptosis induced by benzene metabolites . Cancer Res. , 56 , 5172 – 5178 ( 1996. ). [PubMed] [Google Scholar]
  • 19. ) Williams , G. M.Epigenetic promoting effects of butylated hydroxyanisole . Food Chem. Toxicol. , 24 , 1163 – 1166 ( 1986. ). [DOI] [PubMed] [Google Scholar]
  • 20. ) Imaida , K. , Fukushima , S. , Shirai , T. , Ohtani , M. , Nakanishi , K. and Ito , N.Promoting activities of butylated hydroxyanisole and butylated hydroxytoluene on 2‐stage urinary bladder carcinogenesis and inhibition of γ‐glutamyl transpeptidase‐positive foci development in the liver of rats . Carcinogenesis , 4 , 895 – 899 ( 1983. ). [DOI] [PubMed] [Google Scholar]
  • 21. ) Fukushima , S. , Sakata , T. , Tagawa , Y. , Shibata , M. A. , 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]
  • 22. ) 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]
  • 23. ) Tamano , S. , Fukushima , S. , Shirai , T. , Hirose , M. and Ito , N.Modification by α‐tocopherol, propyl gallate and tertiary butylhydroquinone of urinary bladder carcinogenesis in Fischer F344 rats pretreated with N‐butyl‐N‐(4‐hydroxybutyl)nitrosamine . Cancer Lett. , 35 , 39 – 46 ( 1987. ). [DOI] [PubMed] [Google Scholar]

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

RESOURCES