Organ‐dependent Modifying Effects of Caffeine, and Two Naturally Occurring Antioxidants α‐Tocopherol and n‐Tritriacontane‐16,18‐dione, on 2‐Amino‐1‐methyl‐6‐phenylimidazo [4,5‐b] pyridine (PhIP)‐induced Mammary and Colonic Carcinogenesis in Female F344 Rats

Modifying effects of caffeine, α‐tocopherol, and n‐tritriacontane‐16,18‐dione (TTAD) on 2‐amino‐1‐methyl‐6‐phenylimidazo[4,5‐b]pyridine (PhIP)‐induced mammary and colonic carcinogenesis were investigated in female F344 rats. Groups of 20 rats, 6 weeks old, were given 0.02% PhIP (in diet) alone, or together with 0.1% caffeine (in drinking water), 0.5%α‐tocopherol (in diet) or 0.1% TTAD (in diet) for up to 54 weeks. Groups of 10 females receiving basal diet or one of the test chemicals without PhIP supplementation were also maintained. The final combined incidences (adenomas plus adenocarcinomas) and multiplicity (No./rat) of mammary adenomas and adenocarcinomas were significantly lowered in the PhIP plus caffeine group (10%, 0.10) as compared to the PhIP alone value (40%, 0.50). Incidences of mammary tumors in the PhIP plus α‐tocopherol or TTAD groups tended to be decreased while their multiplicities were significantly lowered. With regard to colon tumor development, on the other hand, rats given PhIP plus caffeine exhibited an elevated incidence (75% versus 15% in the control), whereas α‐tocopherol and TTAD had no effect. Surprisingly, metabolic activation of PhIP was inhibited by addition of caffeine in an in vitro assay. The results indicate that caffeine exerts a potent chemopreventive action against PhIP‐induced mammary carcinogenesis, but acts as a co‐carcinogen for PhIP‐induced colonic carcinogenesis.