Carcinogenesis, Vol 19, 207-212, Copyright © 1998 by Oxford University Press
M Hirose, Y Takesada, H Tanaka, S Tamano, T Kato and T Shirai
The carcinogenicity of low dietary levels of the antioxidants butylated
hydroxyanisole (BHA), caffeic acid, sesamol, 4-methoxyphenol (4-MP) and
catechol, known to target the forestomach or glandular stomach, were
examined alone or in combination in a 2-year long-term experiment and their
modifying effects assessed in a medium-term multiorgan model. In the
carcinogenicity study, groups of 30-31 male F344 rats were treated with
0.4% BHA, 0.4% caffeic acid, 0.4% sesamol, 0.4% 4-MP and 0.16% catechol
either alone or in combination for up to 104 weeks and then killed. In the
medium-term multi-organ model, groups of 10 to 15 male F344 rats were given
diethylnitrosamine (DEN), N-methylnitrosourea (MNU), 1,2-dimethylhydrazine
(DMH), N-butyl-N-(4- hydroxybutyl)nitrosamine (BBN) and
2,2'-dihydroxy-di-n- propylnitrosamine (DHPN) for a total multiple
initiation period of 4 weeks (DMBDD treatment). BHA, caffeic acid, sesamol
and 4-MP, each at doses of 0.4% or 0.08%, and catechol at doses of 0.16% or
0.032% were administered in the diet either alone or in combination after
completion of the initiation regimen. All surviving animals were killed at
the end of week 28, and major organs were examined histopathologically. In
the carcinogenicity study, slightly increased incidences of forestomach
papillomas were found in the sesamol- (15.8%), caffeic acid- (14.8%),
catechol- (3%) and 4-MP- (11.5%) treated groups as compared with basal diet
(0%), and a significant increase was observed with the five antioxidants in
combination (42.9%, P < 0.001). In a medium-term multiorgan
carcinogenesis model, incidences of forestomach papillomas and/or
carcinomas were increased in each high dose group, but additive or
synergistic effects were not found in the combination group. In the low
dose case, the incidence of forestomach papillomas was significantly
increased only in the combination group. With regard to other organs, the
incidence of colon tumors was significantly decreased only in the high dose
combination group. The results indicate that even at low dose levels
phenolic compounds can exert additive/synergistic effect on carcinogenesis.
ARTICLES
Carcinogenicity of antioxidants BHA, caffeic acid, sesamol, 4- methoxyphenol and catechol at low doses, either alone or in combination, and modulation of their effects in a rat medium-term multi- organ carcinogenesis model
First Department of Pathology, Nagoya City University, Medical School, Japan.
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