Itoh Toshiaki, Kuwahara Tomomi, Suzuki Takayoshi, Hayashi Makoto, Ohnishi Yoshinari
Department of Molecular Bacteriology, Graduate School of Medicine, The University of Tokushima, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan.
Mutat Res. 2003 Aug 5;539(1-2):99-108. doi: 10.1016/s1383-5718(03)00134-7.
Transgenic mouse assays have revealed that the mouse intestine, despite its resistance to carcinogenesis, is sensitive to the mutagenicity of some heterocyclic amines (HCAs). Little is known, however, about the level and localization of that sensitivity. We assessed the mutagenicity of four orally administered (20 mg/kg per day for 5 days) HCAs-2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) hydrochloride, 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ), and 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2) acetate-in the intestine of male MutaMice. Two weeks after the last administration, we isolated epithelium from the small intestine, cecum, and colon and analyzed lacZ and cII transgene mutations. PhIP increased the lacZ mutant frequency (MF) in all the samples, and in the small intestine, cII and lacZ MFs were comparable. In the cII gene, G:C to T:A and G:C to C:G transversions were characteristic PhIP-induced mutations (which has also been reported for the rat colon, where PhIP is carcinogenic). In the small intestine, PhIP increased the cII MF to four-fold that of the control, but IQ, MeIQ, and Trp-P-2 did not have a significant mutagenic effect. In the cecum, cII MFs induced by IQ and MeIQ were 1.9 and 2.7 times those in the control, respectively. The MF induced by MeIQ in the colon was 3.1 times the control value. Mutagenic potency was in the order PhIP>MeIQ>IQ; Trp-P-2 did not significantly increase the MF in any tissue. The cecum was the most susceptible organ to HCA mutagenicity.
转基因小鼠试验表明，尽管小鼠肠道对致癌作用具有抗性，但对某些杂环胺（HCA）的致突变性敏感。然而，关于这种敏感性的水平和定位却知之甚少。我们评估了四种经口给予（每天20mg/kg，持续5天）的HCA——2-氨基-1-甲基-6-苯基咪唑[4,5-b]吡啶（PhIP）盐酸盐、2-氨基-3-甲基咪唑[4,5-f]喹啉（IQ）、2-氨基-3,4-二甲基咪唑[4,5-f]喹啉（MeIQ）和3-氨基-1-甲基-5H-吡啶并[4,3-b]吲哚（Trp-P-2）乙酸盐——对雄性Muta小鼠肠道的致突变性。在最后一次给药两周后，我们从小肠、盲肠和结肠中分离出上皮细胞，并分析了lacZ和cII转基因突变。PhIP增加了所有样本中的lacZ突变频率（MF），并且在小肠中，cII和lacZ的MF相当。在cII基因中，G:C到T:A和G:C到C:G的颠换是PhIP诱导的特征性突变（在大鼠结肠中也有报道，在那里PhIP具有致癌性）。在小肠中，PhIP将cII MF增加到对照的四倍，但IQ、MeIQ和Trp-P-2没有显著的致突变作用。在盲肠中，IQ和MeIQ诱导的cII MF分别是对照的1.9倍和2.7倍。MeIQ在结肠中诱导的MF是对照值的3.1倍。致突变效力顺序为PhIP>MeIQ>IQ；Trp-P-2在任何组织中均未显著增加MF。盲肠是对HCA致突变性最敏感的器官。
