Ishiguro Y, Ochiai M, Sugimura T, Nagao M, Nakagama H
Biochemistry and Carcinogenesis Divisions, National Cancer Center Research Institute, 1-1 Tsukiji 5, Chuo-ku, Tokyo 104-0045, Japan.
Carcinogenesis. 1999 Jun;20(6):1063-8. doi: 10.1093/carcin/20.6.1063.
2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), the most abundant mutagenic heterocyclic amine contained in cooked food, induces colon tumors in F344 male rats when administered orally. In the present study, PhIP was introduced to various rat strains, and susceptibility to the induction of aberrant crypt foci (ACFs) was analyzed as a biomarker for colon carcinogenesis. BUF/Nac rats were highly susceptible, giving rise to 12.2 +/- 1.7 ACFs per rat. F344 rats were intermediate and ACI/N rats were resistant, giving 3.5 +/- 1.8 and 0.9 +/- 0.7 ACFs per rat, respectively. In spite of this, the extent of DNA damage by PhIP in F344, in terms of the level of PhIP-DNA adducts, was significantly lower than that in ACI/N. The differences in formation of ACFs could be, in some part, implicated in the differential susceptibility to colon carcinogenesis induced by PhIP, especially in a step later than adduct formation. In an attempt to determine the genetic factors implicated in the susceptibility to formation of ACFs, a possible involvement of the adenomatous polyposis gene (Apc) and its modifier secretory phospholipase A2 (Pla2g2a) was analyzed. No genetic polymorphisms in either Apc or Pla2g2a showed a significant correlation to susceptibility to formation of ACFs among rat strains.
2-氨基-1-甲基-6-苯基咪唑并[4,5-b]吡啶（PhIP）是烹饪食物中含量最丰富的致突变性杂环胺，经口服给予F344雄性大鼠时可诱发结肠肿瘤。在本研究中，将PhIP引入各种大鼠品系，并分析其对异常隐窝灶（ACF）诱导的易感性，将其作为结肠癌发生的生物标志物。BUF/Nac大鼠高度易感，每只大鼠产生12.2±1.7个ACF。F344大鼠为中度易感，ACI/N大鼠具有抗性，每只大鼠分别产生3.5±1.8个和0.9±0.7个ACF。尽管如此，就PhIP-DNA加合物水平而言，F344大鼠中PhIP引起的DNA损伤程度明显低于ACI/N大鼠。ACF形成的差异在一定程度上可能与PhIP诱导的结肠癌发生易感性差异有关，尤其是在加合物形成之后的阶段。为了确定与ACF形成易感性相关的遗传因素，分析了腺瘤性息肉病基因（Apc）及其修饰因子分泌型磷脂酶A2（Pla2g2a）可能的参与情况。Apc或Pla2g2a的基因多态性与大鼠品系中ACF形成的易感性均无显著相关性。
