The carcinogenic significance of reactive intermediates derived from 3-acetoxy- and 5-acetoxy-2-hydroxy-N-nitrosomorpholine.
The carcinogenic significance of reactive intermediates derived from 3-acetoxy- and 5-acetoxy-2-hydroxy-N-nitrosomorpholine.
复制标题
衍生自 3-乙酰氧基-和 5-乙酰氧基-2-羟基-N-亚硝基吗啉的反应中间体的致癌意义。
DOI：
10.1021/tx0502037
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发表时间：
2005
期刊：
影响因子：
--
通讯作者：
Park,Misun
中科院分区：
文献类型：
--
作者：
Loeppky,RichardN;Sukhtankar,Sunil;Gu,Feng;Park,Misun
N-Nitroso-2-hydroxymorpholine (NHMOR), a relatively reactive metabolite of two potent carcinogens,N-nitrosodiethanolamine (NDELA) andN-nitrosomorpholine (NMOR), has been reported to not be carcinogenic. Two isomeric acetate esters of the α-hydroxynitrosamines expected to be produced from the cytochrome P450-mediated metabolism of NHMOR have been synthesized, and their hydrolytic decomposition products, hydrolysis rates, and deoxyguanosine (dG) reaction adducts have been determined.N-Nitroso-3-acetoxy-2-hydroxymorpholine was prepared in high yield from the reaction ofN-nitroso-2,3-dehydromorpholine with dry peracetic acid in glacial acetic acid or by the reaction of its dimethyldioxirane-produced epoxide with glacial acetic acid. The hydrolysis of this α-acetoxynitrosamine gave acetaldehyde (10%), ethylene glycol (55%), glyoxal (95%), and acetic acid. The pH rate profile for the hydrolysis of this nitrosamine was abnormal in that it exhibited pronounced base-catalyzed hydrolysis beginning at pH 5. The mechanism of hydrolytic decomposition is proposed to involve neighboring group participation with the formation of a reactive epoxide intermediate.N-Nitroso-3-acetoxy-2-hydroxymorpholine reacted with dG to give these guanine adducts after acidic deglycosylation: 1,N2-glyoxal (65%), 7-(2-hydroxyethyl)guanine (9%), and O6-hydroxyethylguanine (3%).N-Nitroso-5-acetoxy-2-hydroxymorpholine was synthesized from 2-hydroxyethylvinylnitrosamine by its oxidative conversion to the corresponding aldehyde followed by reaction with dry peracetic acid in glacial acetic. The hydrolytic decomposition products of this nitrosamine were 2-acetoxyacetaldehyde (65%), a rearrangement product, glycol aldehyde (15%), a trace of glyoxal, and acetic acid. The pH rate profile for the hydrolysis of this acetate is similar to other α-acetoxynitrosamines in that it exhibits a pH-independent region which gives way to base-catalyzed ester hydrolysis beginning at pH 7. The lower pH (≈ 7 < 9) onset of base catalysis is proposed to involve base-catalyzed opening of the hemiacetal and intramolecular acyl transfer to give an unstable α-hydroxynitrosamine.N-Nitroso-5-acetoxy-2-hydroxymorpholine was less reactive toward dG and gave the 1,N2-etheno-dG adduct (44%). The products from both of the isomeric α-acetoxy nitrosamines were judged to arise from diazonium ions produced from unstable α-hydroxynitrosamine intermediates. The high yield of the rearrangement product 2-acetoxyacetaldehyde could explain the low carcinogenic potential of NHMOR if it is mainly α-hydroxylated at the 5 carbon. Hydroxylation of NHMOR at carbon 3 is expected to yield a carcinogenic outcome.
