Intestinal toxicity and carcinogenic potential of the food mutagen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in DNA repair deficient XPA-/- mice.
Intestinal toxicity and carcinogenic potential of the food mutagen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in DNA repair deficient XPA-/- mice.
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食物诱变剂 2-氨基-1-甲基-6-苯基咪唑[4,5-b]吡啶 (PhIP) 对 DNA 修复缺陷 XPA-/- 小鼠的肠道毒性和致癌潜力。
DOI：
10.1093/carcin/22.4.619
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发表时间：
2001
期刊：
影响因子：
4.7
通讯作者：
vanKreijl,CF
中科院分区：
文献类型：
--
作者：
Klein,JC;Beems,RB;Zwart,PE;Hamzink,M;Zomer,G;vanSteeg,H;vanKreijl,CF
本文研究了食物诱变剂2-amino-1-methyl-6-phenylimidazo[4，5-b]pyridine(PhIP)对DNA修复缺陷小鼠的作用。缺乏功能性核苷酸切除修复(NER)途径的nullizygousXPA基因敲除小鼠暴露在从10到200 p.p.m的饮食浓度中。结果表明，PhIP对XPA-/-小鼠具有极强的毒性，即使剂量比野生型C57BL/6小鼠耐受的剂量低10倍。XPA-/-小鼠体重迅速下降，并分别在200和100 ppm后的2周和6周内死亡。肠道异常，如膨胀和充盈的回肠和盲肠，再加上明显的饥饿迹象，表明小肠是严重毒性影响的主要目标组织。对携带alacZ报告基因的XPA-/-小鼠的突变分析表明，PhIP的观察到的毒性可能是由小肠的遗传毒性作用引起的。在处理XPA-/-小鼠的肠道DNA中，LacZ突变频率似乎选择性地和剂量依赖性地增加。此外，DNA修复缺陷的XPC-/-小鼠仍然能够修复活跃转录基因中的DNA损伤，在PhIP(100p.p.m)治疗下没有表现出任何毒性。提示活性基因DNA损伤的转录偶联修复(PhIP加合物)在预防PhIP的肠道毒性中起着关键作用。最后，在亚毒性剂量下，PhIP似乎对XPA-/-小鼠具有致癌作用。在给小鼠治疗6个月后，晚上10点或25点。PhIP，在总观察期一年后观察到肿瘤发生率显著增加。晚上10点。只有淋巴瘤被发现，而在晚上25点。一些肠道肿瘤(腺瘤和腺癌)也被观察到。
The effects of the food mutagen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) were studied in DNA repair deficientXPA–/–mice. The nullizygousXPA-knockout mice, which lack a functional nucleotide excision repair (NER) pathway, were exposed to dietary concentrations ranging from 10 to 200 p.p.m. The results show that PhIP is extremely toxic toXPA–/–mice, even at doses 10-fold lower than tolerated by wild-type C57BL/6 mice.XPA–/–mice rapidly lost weight and died within 2 and 6 weeks upon administration of 200 and 100 p.p.m., respectively. Intestinal abnormalities like distended and overfilled ileum and caecum, together with clear signs of starvation, suggests that the small intestines were the primary target tissue for the severe toxic effects. Mutation analysis inXPA–/–mice carrying alacZreporter gene, indicated that the observed toxicity of PhIP might be caused by genotoxic effects in the small intestine.LacZmutant frequencies appeared to be selectively and dose-dependently increased in the intestinal DNA of treatedXPA–/–mice. Furthermore, DNA repair deficientXPC–/–mice, which are still able to repair DNA damage in actively transcribed genes, did not display any toxicity upon treatment with PhIP (100 p.p.m.). This suggests that transcription coupled repair of DNA damage (PhIP adducts) in active genes plays a crucial role in preventing the intestinal toxicity of PhIP. Finally, PhIP appeared to be carcinogenic forXPA–/–mice at subtoxic doses. Upon treatment of the mice for 6 months with 10 or 25 p.p.m. PhIP, significantly increased tumour incidences were observed after a total observation period of one year. At 10 p.p.m. only lymphomas were found, whereas at 25 p.p.m. some intestinal tumours (adenomas and adenocarcinomas) were also observed.