IDENTIFICATION OF N-(DEOXYGUANOSIN-8-YL)-2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE AS THE MAJOR ADDUCT FORMED BY THE FOOD-BORNE CARCINOGEN, 2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE, WITH DNA
IDENTIFICATION OF N-(DEOXYGUANOSIN-8-YL)-2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE AS THE MAJOR ADDUCT FORMED BY THE FOOD-BORNE CARCINOGEN, 2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE, WITH DNA
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DOI：
10.1021/tx00029a016
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发表时间：
1992-09-01
影响因子：
4.1
通讯作者：
KADLUBAR, FF
中科院分区：
文献类型：
--
作者：
LIN, DX;KADERLIK, KR;KADLUBAR, FF
在体外和体内研究了食源性致癌物2-氨基-1-甲基-6-苯基咪唑[4,5-b]吡啶（PhIP）的n -乙酰氧基、n -羟基和硝基衍生物与2'-脱氧核糖核苷或DNA的共价结合。N-乙酰氧基- phip与脱氧鸟苷（dG）反应生成N-（脱氧鸟苷-8-基）- phip (dG- c8 - phi]P)，其结构通过核磁共振和质谱分析、紫外吸收和ph -溶剂分配特征确定。在pH 5.0条件下，n -乙酰氧基-PhIP与小牛胸腺DNA的结合残基数为5.38 +/- 1.16 nmol /mg DNA，而在相同条件下，n -羟基-PhIP的结合残基数仅为0.13-0.23 nmol /mg DNA。在这些条件下，硝基phip没有产生可检测到的结合。对n -乙酰氧基-PhIP修饰的酶解DNA 1-丁醇提取物进行HPLC分析，发现其主要加合物与真正的dG-C8-PhIP共洗脱，具有紫外吸收，质谱与真正的dG-C8-PhIP相同。p -32-标记后分析从口服处理大鼠的结肠、胰腺、肺、心脏和肝脏中分离的DNA，发现存在一个主要的PhIP-DNA加合物。该加合物与p -32标记的dG-C8-PhIP的双（磷酸）衍生物具有相同的色谱性质，占总加合物的35- 45%。因此，这些结果表明PhIP与其他致癌芳香胺类似，在体外通过n -乙酰氧基-PhIP与DNA反应形成dG-C8-PhIP作为主要的DNA加合物，并且在体内口服PhIP后在各种大鼠组织中也是如此。
The covalent binding of the N-acetoxy-, N-hydroxy-, and nitro derivatives of the food-borne carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) to 2'-deoxyribonucleosides or DNA was investigated in vitro and in vivo. N-Acetoxy-PhIP reacted with deoxyguanosine (dG), but not with the other deoxyribonucleosides, to form N-(deoxyguanosin-8-yl)-PhIP (dG-C8-PhI]P), whose structure was determined by NMR and mass spectral analyses and by ultraviolet absorption and pH-solvent partitioning characteristics. While reaction of N-acetoxy-PhIP with calf thymus DNA at pH 5.0 yielded 5.38 +/- 1.16 nmol of bound PhIP residues/mg of DNA, N-hydroxy-PhIP gave only 0.13-0.23 nmol binding/mg of DNA under identical reaction conditions. Nitro-PhIP produced no detectable binding under these conditions. HPLC analysis of 1-butanol extracts of enzymatically hydrolyzed DNA that had been modified by N-acetoxy-PhIP PhIP in vitro showed a major adduct which coeluted with and had an ultraviolet absorption and a mass spectrum that were identical to that of authentic dG-C8-PhIP. P-32-Postlabeling analysis of DNA isolated from colon, pancreas, lung, heart, and liver of rats treated orally with revealed the presence of a major PhIP-DNA adduct. This adduct had chromatographic properties identical to that of the P-32-labeled bis(phosphate) derivative of dG-C8-PhIP and represented 35-45 % of the total adducts. Thus, these results indicate that PhIP is similar to other carcinogenic aromatic amines, forming dG-C8-PhIP as a major DNA adduct in vitro by reaction of N-acetoxy-PhIP with DNA and also in vivo in a variety of rat tissues after oral dosing with PhIP.