Tsuda H, Sekine K, Uehara N, Takasuka N, Moore M A, Konno Y, Nakashita K, Degawa M
Experimental Pathology and Chemotherapy Division, National Cancer Center Research Institute, Tokyo, Japan.
Cancer Lett. 1999 Sep 1;143(2):229-34. doi: 10.1016/s0304-3835(99)00130-5.
In order to elucidate whether mixed exposure to environmental carcinogens and caffeine increases the risk of cancer induction, we investigated the relationship between preneoplastic lesion development in the liver and colon and drug metabolizing enzyme induction and DNA adduct formation, in rats treated with a mixture of heterocyclic amines (HCAs) and caffeine. In Experiment 1, male F344 rats were administered 3 different HCAs, the food carcinogens, 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), alone or in combinations of 2 or 3 at 50 ppm in the diet for 16 weeks. The numbers of hepatic glutathione-S-transferase P form positive (GST-P+) foci and colonic aberrant crypt foci (ACF) were greater in the IQ + MeIQx group than expected from simple summation and increased levels of HCA-DNA adducts were noted. However, no summation was obtained when combined with PhIP, which rather caused inhibition. In Experiment 2, the effects of concurrent caffeine administration on the PhIP carcinogenicity were assessed. Caffeine at 1000 and 500 ppm in the drinking water for 2 weeks significantly increased levels of CYP1A2. Ten weeks concurrent administration of caffeine (1000 ppm) and PhIP (400 ppm) resulted in significant increase of colon ACFs and CYP1A2 expression. Thus, concurrent administration of IQ and MeIQx caused elevation of their carcinogenicity but other mixtures with PhIP did not enhance carcinogenicity. However, a non-carcinogen, caffeine, enhanced PhIP colon carcinogenesis, possibly due to induction of CYP1A2.
为了阐明环境致癌物与咖啡因的混合暴露是否会增加致癌风险，我们研究了用杂环胺（HCA）和咖啡因混合物处理的大鼠肝脏和结肠中癌前病变的发展与药物代谢酶诱导及DNA加合物形成之间的关系。在实验1中，雄性F344大鼠分别单独或按2种或3种组合给予3种不同的HCA，即食物致癌物2-氨基-3-甲基咪唑[4,5-f]喹啉（IQ）、2-氨基-3,8-二甲基咪唑[4,5-f]喹喔啉（MeIQx）和2-氨基-1-甲基-6-苯基咪唑[4,5-b]吡啶（PhIP），剂量为饮食中50 ppm，持续16周。IQ + MeIQx组的肝脏谷胱甘肽-S-转移酶P型阳性（GST-P+）灶和结肠异常隐窝灶（ACF）数量比简单相加预期的要多，并且观察到HCA-DNA加合物水平升高。然而，与PhIP联合时未出现相加效应，反而导致抑制作用。在实验2中，评估了同时给予咖啡因对PhIP致癌性的影响。饮用水中1000 ppm和500 ppm的咖啡因持续2周可显著提高CYP1A2水平。咖啡因（1000 ppm）和PhIP（400 ppm）同时给药10周导致结肠ACF和CYP1A2表达显著增加。因此，IQ和MeIQx同时给药会提高它们的致癌性，但与PhIP的其他混合物不会增强致癌性。然而，一种非致癌物咖啡因增强了PhIP的结肠致癌作用，可能是由于诱导了CYP1A2。
