Souliotis Vassilis L, Henneman John R, Reed Carl D, Chhabra Saranjit K, Diwan Bhalchandra A, Anderson Lucy M, Kyrtopoulos Soterios A
National Hellenic Research Foundation, Institute of Biological Research and Biotechnology, 48 Vassileos Constantinou Avenue, Athens 11635, Greece.
Mutat Res. 2002 Mar 20;500(1-2):75-87. doi: 10.1016/s0027-5107(01)00301-3.
Exposure of rats to the hepatocarcinogen N-nitrosodimethylamine (NDMA) (0.2-2.64 ppm in the drinking water) for up to 180 days resulted in rapid accumulation of N7- and O6-methylguanine in liver and white blood cell DNA, maximum adduct levels being reached within 1-7 days, depending on the dose. The levels of both adducts remained constant up to treatment day 28, subsequently declining slowly to about 40% of maximal levels for the liver and 60% for white blood cells by day 180. In order to elucidate the role of DNA replication in NDMA hepatocarcinogenesis, changes in liver cell labeling index (LI) were also measured on treatment days 21, 120 and 180. Although the time- and dose-dependence of the observed effects were complex, a clear trend towards increased rates of hepatocyte LI, as indicated by BrdU incorporation, with increasing NDMA doses was evident, particularly above 1 ppm, a concentration above which NDMA hepatocarcinogenicity is known to increase sharply. In contrast, no increase in Kupffer cell DNA replication was found at any of the doses employed, in accordance with the low susceptibility of these cells to NDMA-induced carcinogenesis. No significant increase in the occurrence of necrotic or apoptotic cells was noted under the treatment conditions employed. These results suggest that, in addition to the accumulation of DNA damage, alterations in hepatocyte DNA replication during the chronic NDMA exposure may influence the dose-dependence of its carcinogenic efficacy.
将大鼠暴露于肝癌致癌物N-亚硝基二甲胺（NDMA）（饮用水中浓度为0.2 - 2.64 ppm）长达180天，导致肝脏和白细胞DNA中N7-甲基鸟嘌呤和O6-甲基鸟嘌呤迅速积累，根据剂量不同，在1 - 7天内达到最大加合物水平。两种加合物的水平在治疗第28天前保持恒定，随后缓慢下降，到第180天时，肝脏中的加合物水平降至最大水平的约40%，白细胞中的加合物水平降至最大水平的60%。为了阐明DNA复制在NDMA肝癌发生中的作用，还在治疗第21天、120天和180天测量了肝细胞标记指数（LI）的变化。尽管观察到的效应的时间和剂量依赖性很复杂，但随着NDMA剂量增加，通过BrdU掺入表明肝细胞LI率增加的明显趋势很明显，特别是在1 ppm以上，已知在该浓度以上NDMA致癌性会急剧增加。相比之下，在所采用的任何剂量下均未发现库普弗细胞DNA复制增加，这与这些细胞对NDMA诱导的致癌作用的低敏感性一致。在所采用的治疗条件下，未观察到坏死或凋亡细胞的发生率有显著增加。这些结果表明，除了DNA损伤的积累外，慢性NDMA暴露期间肝细胞DNA复制的改变可能会影响其致癌效力的剂量依赖性。
