Dosimetry of O6-methylguanine in rat DNA after low-dose, chronic exposure to N-nitrosodimethylamine (NDMA). Implications for the mechanism of NDMA hepatocarcinogenesis.
Dosimetry of O6-methylguanine in rat DNA after low-dose, chronic exposure to N-nitrosodimethylamine (NDMA). Implications for the mechanism of NDMA hepatocarcinogenesis.
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DOI：
10.1093/carcin/16.10.2381
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发表时间：
1995-10
期刊：
影响因子：
4.7
通讯作者：
Vassiis L. Souliotis;S. K. Chhabra;L. Anderson;S. Kyrtopoulos
中科院分区：
文献类型：
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作者：
Vassiis L. Souliotis;S. K. Chhabra;L. Anderson;S. Kyrtopoulos
实验开始时，6周龄或7个月龄的Wistar Furth/NCr雌性大鼠连续28天饮用含有n -亚硝基二甲胺（NDMA）的水，浓度范围为0.2-2.64 p.m， 10周龄时，NDMA的日摄入量为28-372微克/kg/天。在暴露期间的不同时间以及停止暴露后立即测量肝脏和血液白细胞DNA中诱变前DNA加合物o6 -甲基鸟嘌呤（O6-meG）的水平。该加合物在两种组织中迅速积累，在2-7天内达到0.08-0.45 μ mol/mol / g的稳定状态，在幼龄和成年动物中相似。血白细胞中O6-meG的积累比肝脏低约30%。停止NDMA治疗后，两种组织DNA中的加合物迅速丢失，肝脏的加合物丢失时间约为19-23小时，血液白细胞的加合物丢失时间为30-35小时。在整个治疗过程中，肝脏o6 -烷基鸟嘌呤- dna烷基转移酶（AGT）未发生变化。稳态加合物水平与NDMA剂量率近似线性相关，除了在剂量率> 0.4 p.p.m（约56微克/千克/天）时观察到明显的中断（对应于2.6倍的低斜率）。这种剂量-反应关系与Peto等人（Cancer Res., 51,6415 -6451）报道的用相似浓度的NDMA长期治疗的大鼠肝肿瘤诱导的急剧增加形成对比，表明O6-meG的积累本身不能解释NDMA在大鼠中的致癌作用。在上述慢性暴露研究期间（25、50或100微克/千克），单剂量NDMA ig后，肝脏和血液白细胞中O6-meG的修复遵循明显的双相动力学。在肝脏中，尽管AGT没有任何变化，但最初的快速期（t1/2约1.5-1.7小时）之后是更慢的修复期（t1/2约20.7-24.9小时）。将修复动力学的两个片段追溯到0时间的外推表明，大约52-61%最初在肝脏中形成的加合物和33-35%在血液白细胞中形成的加合物属于快速修复的类别。（摘要删节为400字）
Groups of female Wistar Furth/NCr rats, aged 6 weeks or 7 months at the start of the experiment, were administered drinking water containing N-nitrosodimethylamine (NDMA) for up to 28 days at concentrations in the range 0.2-2.64 p.p.m., resulting in daily intakes in the range 28-372 micrograms/kg/day at age 10 weeks. The levels of the premutagenic DNA adduct O6-methylguanine (O6-meG) in liver and blood leukocyte DNA were measured at different times during this exposure as well as on the days immediately following cessation of exposure. The adduct was found to accumulate rapidly in both tissues, reaching within 2-7 days steady states in the range 0.08-0.45 mumol/molG, similar in young and adult animals. Accumulation of O6-meG in blood leukocytes was approximately 30% lower than in the liver. Following cessation of NDMA treatment, adducts were lost rapidly from the DNA of both tissues, with an apparent t1/2 of approximately 19-23 h for the liver and 30-35 h for blood leukocytes. No change in liver O6-alkylguanine-DNA alkyltransferase (AGT) took place throughout this treatment. The steady-state adduct levels were approximately linearly related to NDMA dose-rate, except that a clear break (corresponding to a 2.6-fold lower slope) was observed at dose rates > 0.4 p.p.m. (approximately 56 micrograms/kg/day). This dose-response relationship is in contrast to the sharp increase in the liver tumour induction in rats chronically treated with similar concentrations of NDMA reported by Peto et al. (Cancer Res., 51, 6415-6451) and suggests that accumulation of O6-meG cannot by itself account for the hepatocarcinogenic efficacy of NDMA in the rat. Following i.g. administration of single doses of NDMA in a range approximately corresponding to the daily intake during the above mentioned chronic exposure study (25, 50 or 100 micrograms/kg), repair of O6-meG followed sharply biphasic kinetics in both liver and blood leukocytes. In the liver, an initial rapid phase (t1/2 approximately 1.5-1.7 h) was followed by much slower repair (t1/2 approximately 20.7-24.9 h) despite the absence of any change in AGT. Extrapolation of the two segments of the repair kinetics plots back to 0 time suggests that approximately 52-61% of the adducts originally formed in the liver and 33-35% of those formed in blood leukocytes belonged to the rapidly repaired category.(ABSTRACT TRUNCATED AT 400 WORDS)