Chemopreventive effects of the antioxidants 1-O-hexyl-2,3,5- trimethylhydroquinone (HTHQ), 3-O-ethylascorbic acid (EAsA), 3-O-dodecylcarbomethylascorbic acid (DAsA), green tea catechins (GTC) and ellagic acid on 2-amino-1-methyl-6- phenylimidazo[4,5-b]pyridine (PhIP)-induced mammary carcinogenesis were examined in female F344 rats. Groups of 20-21 6-week-old rats were maintained on a powdered diet containing 0.02% PhIP alone, PhIP together with 0.5% HTHQ, 1% EAsA, 1% DAsA, 1% GTC or 0.1% ellagic acid, these antioxidants alone or basal diet alone without supplement for 52 weeks. The survival rates of PhIP plus antioxidant groups at the end of the experiment were higher than that of the PhIP alone group. Sequential observation of palpable mammary tumors demonstrated only one tumor by week 52 in the PhIP plus HTHQ group, whereas 40% of the rats receiving PhIP alone had tumors by this time point. The final incidence of mammary adenocarcinomas was significantly decreased in the PhIP plus HTHQ group (4.8%, P < 0.01) as compared to the PhIP alone value (40%). Although statistically not significant, incidences of adenocarcinomas in the other antioxidant-treated groups (23.8-28.6%) were also lower than in the PhIP alone group. Furthermore, the incidence of large intestinal tumors in the PhIP plus HTHQ group (0%) showed a tendency to decrease relative to the PhIP alone group (16.7%). These results indicate that antioxidants, particularly HTHQ, exert a potent chemopreventive action against PhIP-induced carcinogenesis.
Male F344 rats were administered 2‐amino‐3,8‐dimethylimidazo[4,5‐f]quinoxaline (MeIQx) in the diet at doses of 200, 50, 12.5, 3.2, 0.8, 0.2 and 0.05 ppm for 6 weeks, and partially hepatectomized 1 week after the beginning of MeIQx administration. Quantitative values for glutathione S‐transferase placental form (GST‐P)‐positiye foci in the liver were dose‐dependently increased by the MeIQx treatment. 8‐Hydroxyguanine (8‐OHG) levels assessed after 1 week of dietary MeIQx administration were also dose‐dependently increased, although the effect was no longer observed at the end of the treatment period. The correlation between numbers of GST‐P‐positive foci at week 6 and 8‐OHG levels at week 1 was linear, values for both parameters being higher than the control levels even in the 0.8 ppm dose group. These findings indicate that, in addition to the previously reported MeIQx‐DNA adduct formation, DNA modifications due to oxidative damage may play an important role in MeIQx liver carcinogenesis in rats.
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