REACTION OF ALPHA-ACETOXY-N-NITROSOPIPERIDINE WITH DEOXYGUANOSINE - OXYGEN-DEPENDENT FORMATION OF 4-OXO-2-PENTENAL AND A 1,N2-ETHENODEOXYGUANOSINE ADDUCT
REACTION OF ALPHA-ACETOXY-N-NITROSOPIPERIDINE WITH DEOXYGUANOSINE - OXYGEN-DEPENDENT FORMATION OF 4-OXO-2-PENTENAL AND A 1,N2-ETHENODEOXYGUANOSINE ADDUCT
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DOI：
10.1021/tx00029a018
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发表时间：
1992-09-01
影响因子：
4.1
通讯作者：
CHUNG, FL
中科院分区：
文献类型：
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作者：
HECHT, SS;YOUNGSCIAME, R;CHUNG, FL
六元杂环亚硝胺N-亚硝基哌啶（NPIP）是大鼠食管癌的致癌物，而其五元同系物N-亚硝基吡咯烷（NPYR）是肝脏癌的致癌物。这些截然不同的器官特异性可能是由于NPIP和NPYR在代谢活化为与DNA结合的中间体方面的差异。先前的研究表明，NPYR代谢活化为DNA结合产物是通过α-羟基化发生的。NPIP的DNA加合物尚未表征。因此，我们通过研究α-乙酰氧基NPIP与脱氧鸟苷的反应开始了我们的研究。通过高效液相色谱-紫外检测器检测到的主要加合物通过其UV、H-1-NMR和MS表征为7-（2-氧代丙基）-5，9-二氢-9-氧代-3-β-D-脱氧-γ-呋喃核糖基咪唑并[1，2-a]嘌呤。这种7-（2-氧代丙基）-取代的1，N2-乙烯基脱氧鸟苷加合物通过4-氧代-2-戊烯醛（3-乙酰丙烯醛）与脱氧鸟苷的1和N2位反应形成。由于从α-乙酰氧基NPIP形成4-氧代-2-戊烯醛是出乎意料的，我们更详细地研究了α-乙酰氧基NPIP的溶剂分解。在磷酸盐缓冲液（pH7.0）中于37 ℃孵育α-乙酰氧基NPIP 7-24小时形成的主要产物包括4-氧代-2-戊烯醛（11-21%产率）、4-羟基戊醛（18-22%）和5-羟基戊醛（27-29%）。4-氧代-2-戊烯醛的形成需要O2。本研究的结果表明，α-acetoxyNPIP的化学和由此产生的脱氧鸟苷加合物，这可能与NPIP的致癌活性的一些独特的功能。
The six-membered heterocyclic nitrosamine N-nitrosopiperidine (NPIP) is an esophageal carcinogen in the rat whereas its five-membered homologue N-nitrosopyrrolidine (NPYR) is a liver carcinogen. These contrasting organospecificities may be due to differences between NPIP and NPYR in their metabolic activation to intermediates which bind to DNA. Previous studies have shown that the metabolic activation of NPYR to DNA binding products occurs through alpha-hydroxylation. DNA adducts of NPIP have not been characterized. Therefore, we began our studies by investigating the reaction of alpha-acetoxyNPIP with deoxyguanosine. A major adduct, detected by high-performance liquid chromatography with UV detection, was characterized by its UV, H-1-NMR, and MS as 7-(2-oxopropyl)-5,9-dihydro-9-oxo-3-beta-D-deox-yribofuranosylimidazo[1,2-a]purine. This 7-(2-oxopropyl)-substituted 1,N2-ethenodeoxyguanosine adduct was formed by reaction of 4-oxo-2-pentenal (3-acetylacrolein) with the 1 and N2 positions of deoxyguanosine. Since the formation of 4-oxo-2-pentenal from alpha-acetoxyNPIP was unexpected, we investigated the solvolysis of alpha-acetoxyNPIP in more detail. Major products formed in incubations of a-acetoxyNPIP for 7-24 h in phosphate buffer (pH 7.0) at 37-degrees-C included 4-oxo-2-pentenal (11-21% yield), 4-hydroxypentanal (18-22%), and 5-hydroxy-pentanal (27-29%). The formation of 4-oxo-2-pentenal required O2. The results of this study demonstrate some unique features of the chemistry of alpha-acetoxyNPIP and the resulting deoxyguanosine adducts which may be related to the carcinogenic activity of NPIP.