Nagao M, Sugimura T
Carcinogenesis Division, National Cancer Center Research Institute, Tokyo, Japan.
Mutat Res. 1993 Nov;290(1):43-51. doi: 10.1016/0027-5107(93)90031-a.
The diet contains various mutagens and carcinogens that can be classified into three groups: naturally occurring chemicals, synthetic compounds and compounds produced by cooking. The first group includes mycotoxins and plant alkaloids while the second is exemplified by food additives and pesticides. The third includes polycyclic aromatic hydrocarbons and heterocyclic amines (HCAs). HCAs are mutagenic to microbes and eukaryotes and their precursors are creatine or creatinine, sugars, and amino acids in meat and fish. Among 10 HCAs so far examined for carcinogenicity in rodents, 2-amino-6-methyldipyrido[1,2-a:3',2'-d]imidazole (Glu-P-1), 2-aminodipyrido[1,2-a:3',2'-d]imidazole (Glu-P-2), 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) induced colon cancer in rats. PhIP is an especially interesting compound inducing colon tumors specifically in male F344 rats and only very rarely in females, which develop mammary carcinomas at high frequency instead. Since induced DNA adduct levels, determined by the 32P-postlabeling method, were found to be almost the same in male and female F344 rats adduct formation in itself is not directly responsible for carcinogenesis. We established, however, that PhIP causes increased cell proliferation in colon mucosa but not in the non-target liver or kidney of male rats. Induction of cell proliferation is therefore possibly an additional important factor determining carcinogenic organ specificity. In terms of molecular alteration ras family gene mutations are very rare and no mutations are evident in the p53 gene in colon tumors induced by HCAs. Their development due to HCAs can thus be considered an appropriate experimental model for human colon tumors in which ras or p53 gene activation is not involved. Since HCAs are genotoxic compounds, a causal role in some stage of human colon carcinogenesis is plausible. Exposure to HCAs should accordingly be avoided as far as possible.
这种饮食含有多种诱变剂和致癌物，可分为三类：天然存在的化学物质、合成化合物以及烹饪产生的化合物。第一类包括霉菌毒素和植物生物碱，第二类以食品添加剂和杀虫剂为代表。第三类包括多环芳烃和杂环胺（HCAs）。HCAs 对微生物和真核生物具有诱变性，其前体是肉类和鱼类中的肌酸或肌酐、糖类以及氨基酸。在目前已对啮齿动物进行致癌性检测的 10 种 HCAs 中，2-氨基-6-甲基二吡啶并[1,2-a:3',2'-d]咪唑（Glu-P-1）、2-氨基二吡啶并[1,2-a:3',2'-d]咪唑（Glu-P-2）、2-氨基-3-甲基咪唑并[4,5-f]喹啉（IQ）、2-氨基-3,4-二甲基咪唑并[4,5-f]喹啉（MeIQ）和 2-氨基-1-甲基-6-苯基咪唑并[4,5-b]吡啶（PhIP）在大鼠中诱发了结肠癌。PhIP 是一种特别有趣的化合物，它专门在雄性 F344 大鼠中诱发结肠肿瘤，而在雌性大鼠中很少诱发，雌性大鼠反而高发乳腺癌。通过 32P 后标记法测定发现，雄性和雌性 F344 大鼠中的诱导 DNA 加合物水平几乎相同，因此加合物形成本身并非致癌作用的直接原因。然而，我们确定 PhIP 会导致雄性大鼠结肠黏膜中的细胞增殖增加，但不会导致非靶器官肝脏或肾脏中的细胞增殖增加。因此，细胞增殖的诱导可能是决定致癌器官特异性的另一个重要因素。就分子改变而言，ras 家族基因突变非常罕见，在 HCAs 诱导的结肠肿瘤中，p53 基因也没有明显突变。因此，由 HCAs 导致的肿瘤发生可被视为一种合适的人类结肠肿瘤实验模型，其中不涉及 ras 或 p53 基因激活。由于 HCAs 是遗传毒性化合物，它们在人类结肠癌发生的某些阶段起因果作用是合理的。因此，应尽可能避免接触 HCAs。
