Kinetics of diethylnitrosamine hepatocarcinogenesis in the infant mouse.
Kinetics of diethylnitrosamine hepatocarcinogenesis in the infant mouse.
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发表时间：
1983-09
期刊：
影响因子：
11.2
通讯作者：
S. Vesselinovitch;N. Mihailovich
中科院分区：
文献类型：
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作者：
S. Vesselinovitch;N. Mihailovich
用无毒致癌剂量范围的二乙基亚硝胺（DEN）对15日龄雄性C57 BL/6 J × C3 HeB/FeJ F1小鼠的肝癌发生动力学进行了研究。将致癌物腹膜内注射一次，并根据方案处死动物。两项研究在4年内相继进行。在第一项研究中，各组小鼠分别接受每克体重0.625、1.25、2.5和5.0微克DEN的治疗，每隔10周杀死一组8只小鼠，第一次是在致癌治疗后10周。评价了剂量-反应关系、转化概率以及早期（嗜碱性病灶）和晚期出现的局灶性和结节性肝细胞病变发生率达到50%的剂量-时间。在第二项研究中，用每克体重0.312、0.625、1.25、2.5和5.0微克DEN处理小鼠组，并在第10、16、20、24、30、34、40、45、50、55、60、65、70、75、80、85、80、90、95、100、10致癌处理后90、95、100和110周。使用诱导的嗜碱性病灶和肝细胞癌/风险肝细胞数量（转化概率）来评价剂量-反应、时间-反应和时间-剂量动力学。在这两项研究中，肝癌发生的动力学是根据双对数标度绘制的数据进行评价的。无论使用的剂量，DEN诱导四个不同的形态实体：嗜碱性（葡萄糖-6-磷酸酶缺乏）病灶;增生性结节;肝细胞腺瘤;和肝细胞癌在所有动物。第一项研究证明了单次给药（d）与50%发生率时间（t50%）（d）乘积的正剂量-反应关系和恒定性（k）。Tn 50%= k）。上述四种病变的时间幂（n）数值分别从2.6增加到2.7、3.4和5.7。第二项研究显示了关于嗜碱性病灶和肝细胞癌诱导的一级动力学。嗜碱性病灶发展的转化概率比观察到的肝细胞癌发展的转化概率高出三个数量级，这表明这两种类型的命中之间存在质的差异。时间反应动力学表明，嗜碱性灶和癌的发展与时间因素的2和4的幂分别为这两个病变。时间-剂量关系与固定数量的病变/致癌风险肝细胞数量呈负斜率，诱导嗜碱性病灶的n值为2（d）。t28/10（7）= k）和诱导肝细胞癌的n值4（d . t40.08/10（7）= k）。这些数据表明，至少需要两个关键事件的诱导嗜碱性灶和至少需要四个事件的诱导肝细胞癌。
Kinetics of hepatocarcinogenesis was evaluated in 15-day-old male C57BL/6J X C3HeB/FeJ F1 mice using a nontoxic carcinogenic dose range of diethylnitrosamine (DEN). The carcinogen was injected i.p. once, and the animals were killed according to the protocol. Two studies were carried out sequentially over a period of 4 years. In the first study, groups of mice were treated with 0.625, 1.25, 2.5, and 5.0 micrograms of DEN per g of body weight, and subgroups of eight mice were killed at 10-week intervals, the first at 10 weeks following carcinogenic treatment. The dose-response relationship, transformation probabilities, and the dose versus time to 50% incidence of the early (basophilic foci) and later appearing focal and nodular hepatocellular lesions were evaluated. In the second study, groups of mice were treated with 0.312, 0.625, 1.25, 2.5, and 5.0 micrograms of DEN per g of body weight, and subgroups of 8 to 20 animals were killed at 10, 16, 20, 24, 30, 34, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, and 110 weeks after carcinogenic treatment. The numbers of induced basophilic foci and hepatocellular carcinomas per number of liver cells at risk (transformation probabilities) were used to evaluate dose-response, time-response, and time-dose kinetics. In both studies, the kinetics of hepatocarcinogenesis was evaluated from data plotted on the double logarithmic scale. Regardless of the dose used, DEN induced four distinct morphological entities: basophilic (glucose-6-phosphatase deficient) foci; hyperplastic nodules; hepatocellular adenomas; and hepatocellular carcinomas in all animals. The first study demonstrated a positive dose-response relationship and constancy (k) of the product of single dose (d) and the time to 50% (t50%) incidence (d . tn50% = k) for each of the four morphological entities. The numerical value of the power of time (n) increased from 2.6 to 2.7, 3.4, and 5.7 for the above four lesions, respectively. The second study showed first-order kinetics regarding the induction of basophilic foci and hepatocellular carcinomas. The transformation probability of development of basophilic foci was up to three orders of magnitude greater than that observed for development of hepatocellular carcinomas, suggesting a qualitative difference between these two types of hits. The time-response kinetics showed that the development of basophilic foci and carcinomas was related to the time factor by powers of 2 and 4 for these two lesions, respectively. The time-dose relationship to a fixed number of lesions per number of liver cells at carcinogenic risk showed a negative slope with an n value of 2 for the induction of basophilic foci (d . t28/10(7) = k) and an n value of 4 for the induction of hepatocellular carcinomas (d . t40.08/10(7) = k). The data indicated that at least two critical events are needed for the induction of basophilic foci and at least four events are required for the induction of hepatocellular carcinomas...