Probing the mechanism of the carcinogenic activation of N-nitrosodiethanolamine with deuterium isotope effects: in vivo induction of DNA single-strand breaks and related in vitro assays.
Probing the mechanism of the carcinogenic activation of N-nitrosodiethanolamine with deuterium isotope effects: in vivo induction of DNA single-strand breaks and related in vitro assays.
复制标题
探讨氘同位素作用下 N-亚硝基二乙醇胺的致癌激活机制：体内诱导 DNA 单链断裂及相关体外测定。
DOI：
10.1021/tx9801716
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发表时间：
1998
期刊：
影响因子：
--
通讯作者：
Eisenbrand,G
中科院分区：
文献类型：
--
作者：
Loeppky,RN;Fuchs,A;Janzowski,C;Humberd,C;Goelzer,P;Schneider,H;Eisenbrand,G
A series of bioassays, including in vivo induction of DNA single-strand breaks (SSB) and cytotoxicity in cytochrome P450 2E1-transfected cells, were utilized withN-nitrosodiethanolamine (NDELA), its deuterated isotopomers (α-D4NDELA and β-D4NDELA),N-nitroso-2-hydroxymorpholine (NHMOR), and two of its deuterated isotopomers (2-D-NHMOR and 5,5-D2-NHMOR) to probe the mechanism of carcinogenic activation of NDELA and the role of its metabolite NHMOR. DNA samples, taken from the livers of male Wistar rats 4 h after the administration of NDELA, exhibited dose-dependent DNA SSB levels over the range of 0.08−0.75 mmol/kg (body weight), with the greatest SSB level at the highest dose. Deuterium isotope effects on DNA SSB levels were inversely dependent on dose: α-D4NDELA, 3.22−1.37; and β-D4NDELA, 1.38−0.79. At the lowest dose of 0.15 mmol/kg (body weight), 5,5-D2-NHMOR gave an isotope effect for DNA SSB of 2.8 while that for 2-D-NHMOR was 0.7. NDELA and β-D4NDELA were equally cytotoxic to human P450 2E1-transfected V79 Chinese hamster cells, while α-D4NDELA was not. Significant DNA SSB levels were observed in these cells for NDELA and β-D4NDELA but not for α-D4NDELA. A kinetic deuterium isotope effect of 2.6 forVmax/Kmwas observed for the horse liver alcohol dehydrogenase-mediated oxidation of β-D4NDELA to NHMOR, whilekH/kDfor α-D4NDELA was 1.05. These data provide the first definitive evidence for the activation of NDELA by a pathway involving the scission of the α-CH bond and are consistent with P450 2E1-mediated α-hydroxylation of NDELA producing the corresponding reactive α-hydroxynitrosamine.
