Turteltaub K W, Knize M G, Healy S K, Tucker J D, Felton J S
Biomedical Sciences Division, Lawrence Livermore National Laboratory, Livermore, CA 94550.
Food Chem Toxicol. 1989 Oct;27(10):667-73. doi: 10.1016/0278-6915(89)90121-x.
The toxicokinetics of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), a member of the aminoimidazoazaarene family of mutagens, was studied in C57BL/6 male mice after ip and gavage exposure to a single dose of 100 mg/kg body weight. Twenty-four hr after administration of the dose, 39% of the [14C]PhIP had been found in the urine of the animals exposed ip and 12% had been found in the faeces. By comparison, at 24 hr, gavage-exposed animals had excreted 31% of the administered radioactivity in the urine and 30% in the faeces. Significantly higher levels of labelled compounds could be detected in the blood of animals dosed ip than in that of those dosed by gavage at 6 and 12 hr after dosing. Tissue concentrations of labelled compound were highest in the liver and gastro-intestinal tract of the ip group and the large intestine of the gavage group. Considerable radioactivity was also detected in the contents of the large and small intestine of the ip group suggesting biliary excretion of PhIP. Peak tissue concentrations were found 6-12 hr after administration of the dose by both routes. High-performance liquid chromatography of urine demonstrated the presence of 11 metabolites while only two major metabolites were found in the faeces, one of which was not present in the urine. None of the metabolites appeared to be formed by simple N-acetylations or N-demethylations of PhIP. No differences were seen in the metabolite profiles between the ip and the gavage groups, but significant differences were seen in the kinetics of PhIP excretion between animals dosed by these two routes. These data indicate that the toxicokinetics of PhIP metabolism differ depending on the route of administration and should be considered when performing animal studies to assess the significance of human dietary PhIP consumption.
2-氨基-1-甲基-6-苯基咪唑并[4,5-b]吡啶（PhIP）是诱变剂氨基咪唑氮杂芳烃家族的一员，在给C57BL/6雄性小鼠腹腔注射和灌胃100mg/kg体重的单剂量后，对其毒代动力学进行了研究。给药24小时后，腹腔注射暴露的动物尿液中发现39%的[14C]PhIP，粪便中发现12%。相比之下，在24小时时，灌胃暴露的动物尿液中排出了31%的给药放射性，粪便中排出了30%。给药后6小时和12小时，腹腔注射给药的动物血液中检测到的标记化合物水平明显高于灌胃给药的动物。腹腔注射组肝脏和胃肠道以及灌胃组大肠中标记化合物的组织浓度最高。在腹腔注射组的大肠和小肠内容物中也检测到相当多的放射性，表明PhIP经胆汁排泄。两种给药途径给药后6-12小时发现组织浓度峰值。尿液的高效液相色谱显示存在11种代谢物，而粪便中仅发现两种主要代谢物，其中一种在尿液中不存在。似乎没有一种代谢物是由PhIP的简单N-乙酰化或N-去甲基化形成的。腹腔注射组和灌胃组之间的代谢物谱没有差异，但这两种给药途径给药的动物在PhIP排泄动力学方面存在显著差异。这些数据表明，PhIP代谢的毒代动力学因给药途径而异，在进行动物研究以评估人类饮食中PhIP摄入量的意义时应予以考虑。
