Kaufmann W K, Rice J M, MacKenzie S A, Smith G J, Wenk M L, Devor D, Qaqish B F, Kaufman D G
Department of Pathology, University of North Carolina, Chapel Hill 27599-7295.
Carcinogenesis. 1991 Sep;12(9):1587-93. doi: 10.1093/carcin/12.9.1587.
Hepatocyte proliferation and damage to DNA were characterized during the initiation phase of carcinogenesis in livers of rats that had received a single administration of the methylating agent methyl(acetoxymethyl)nitrosamine (DMN-OAc). Quiescent non-proliferating hepatocytes in intact livers did not appear to be susceptible to initiation by DMN-OAc, whereas proliferating hepatocytes in the S phase appeared to have greatest risk. To characterize the phenomenology of S-phase-dependent initiation further, the fractions of hepatocytes in the S and M phases of the cell cycle were enumerated at various times after treatment with DMN-OAc. Hepatocytes treated when in G1 experienced a delay of up to 20 h in the onset of S phase and a reduced rate of entry into the S and M cycle phases. Hepatocytes treated when in S phase experienced considerable delay in progression to mitosis due to part to inhibition of DNA replication. Hepatocytes treated when in late S/G2 also demonstrated a delay in progression into mitosis. The levels of 7-methylguanine and O6-methyldeoxyguanosine were quantified in the nuclear DNA of proliferating hepatocytes. The kinetics of removal of these lesions appeared to be first-order (half-life = 24 h). Hepatocyte risk of initiation was modeled by a function which summed over time the product of the fraction of hepatocytes in the S phase and the fraction of residual, unrepaired damage to DNA. For hepatocytes treated when in early G1, the time-weighted frequency of premutagenic DNA damage that was present during DNA replication was estimated to be less than half of that for hepatocytes treated when in early S. The results suggest that cell-cycle-dependent variation in sensitivity to initiation of hepatocarcinogenesis may be, in part, due to efficient removal of potentially carcinogenic lesions from DNA during an extended G1. The apparent high sensitivity of hepatocytes in late S/G2 suggests the contribution of additional factors.
在单次给予甲基化剂甲基（乙酰氧甲基）亚硝胺（DMN - OAc）的大鼠肝脏致癌起始阶段，对肝细胞增殖和DNA损伤进行了表征。完整肝脏中静止的非增殖肝细胞似乎不易受到DMN - OAc引发的影响，而处于S期的增殖肝细胞似乎风险最大。为了进一步表征S期依赖性起始的现象学，在用DMN - OAc处理后的不同时间点，对细胞周期S期和M期的肝细胞比例进行了计数。处于G1期时接受处理的肝细胞在S期开始时出现长达20小时的延迟，进入S期和M期的速率降低。处于S期时接受处理的肝细胞由于部分DNA复制受到抑制，在进入有丝分裂过程中出现相当大的延迟。处于S期后期/G2期时接受处理的肝细胞在进入有丝分裂过程中也出现延迟。对增殖肝细胞的核DNA中7 - 甲基鸟嘌呤和O6 - 甲基脱氧鸟苷的水平进行了定量。这些损伤的去除动力学似乎是一级的（半衰期 = 24小时）。肝细胞起始风险通过一个函数进行建模，该函数随时间累加S期肝细胞比例与DNA残留未修复损伤比例的乘积。对于处于G1期早期时接受处理的肝细胞，DNA复制期间存在的致突变前DNA损伤的时间加权频率估计不到处于S期早期时接受处理的肝细胞的一半。结果表明，肝细胞癌起始敏感性的细胞周期依赖性变化可能部分归因于在延长的G1期从DNA中有效去除潜在致癌损伤。S期后期/G2期肝细胞明显的高敏感性表明还有其他因素的作用。
