Involvement of 8-hydroxyguanine formation in the initiation of rat liver carcinogenesis by low dose levels of N-nitrosodiethylamine.
Involvement of 8-hydroxyguanine formation in the initiation of rat liver carcinogenesis by low dose levels of N-nitrosodiethylamine.
复制标题
低剂量 N-亚硝基二乙胺引发大鼠肝癌过程中 8-羟基鸟嘌呤形成的参与。
作者：
D. Nakae;Y. Kobayashi;H. Akai;N. Andoh;H. Satoh;K. Ohashi;M. Tsutsumi;Y. Konishi
用大鼠肝脏模型探讨了8-羟基鸟嘌呤(8-OHG)的形成是否参与了低剂量N-亚硝酸二乙胺(DEN)的启动作用。雄性Fischer 344只大鼠，6周龄，单次ip。DEN的剂量在0.001至100毫克/公斤体重之间。随机抽取大鼠72 h内测定肝DNA中8-OHG的含量。其余大鼠不再接受进一步治疗，于4小时行肝部分切除(PH)，或PH加腹腔注射。第1、3天给予500 mg/kg的秋水仙碱。在第2~4周进行选择，并在第5周通过形成γ-谷氨酰转移酶阳性灶来评估DEN的启动活性。肝脏DNA中的8-OHG水平在第6~72小时显著升高，且呈剂量依赖关系。在非PH组和PH组大鼠中，剂量分别为1-100 mg/kg和0.001-100 mg/kg体重时，均可观察到剂量依赖性的病灶诱导。未服用秋水仙碱的大鼠和服用秋水仙碱的大鼠的病灶大小也显著增大，且分别与1-100 mg/kg体重和0.001-100 mg/kg体重的剂量呈正相关。统计显示，DEN在0.001-0.1m g/kg和1-100m g/kg体重范围内形成8-OHG的线性趋势不同，但在给药后72h内形成的总加合物与终止时病灶的发展密切相关。这些结果表明，即使在低剂量水平下，肝DNA中8-OHG的形成也可能参与了DEN诱发肝癌的发生。0.001-0.1m g/kg和1-100m g/kg的剂量可能产生不同的影响。
The question of whether 8-hydroxyguanine (8-OHG) formation is involved in initiation by low dose levels of N-nitrosodiethylamine (DEN) was addressed using a rat liver model. Male Fischer 344 rats, 6 weeks of age, were administered single i.p. doses of DEN between 0.001 and 100 mg/kg body weight. The 8-OHG levels in liver DNA were measured within 72 h thereafter in randomly selected rats. The remaining rats were given either no further treatment, partial hepatectomy (PH) at hour 4, or PH with i.p. administration of 500 mg/kg body weight of colchicine on days 1 and 3. A selection procedure was performed between weeks 2 and 4, and the initiating activity of DEN was assessed in terms of development of gamma-glutamyltransferase-positive foci at week 5. The 8-OHG levels in the liver DNA were significantly elevated between hours 6 and 72 in a manner dependent on the DEN dose. Dose-dependent induction of foci was similarly noted with doses of 1-100 and 0.001-100 mg/kg body weight in the non-PH and the PH rats, respectively. The sizes of the foci were also significantly increased in a manner dependent on the DEN doses of 1-100 and 0.001-100 mg/kg body weight in the non-colchicine-treated and the colchicine-treated rats, respectively. Statistically, linear trends of 8-OHG formation due to DEN were different at 0.001-0.1 and 1-100 mg/kg body weight, but the total adducts formed within 72 h of the administration proved to be closely related to the development of foci at the termination. These results indicate that 8-OHG formation in the liver DNA may be involved in DEN initiation of hepatocarcinogenesis even at low dose levels, and that single i.p. doses of 0.001-0.1 and 1-100 mg/kg body weight might exert different effects.
影响因子：
64.8
作者：
KUCHINO, Y;MORI, F;NISHIMURA, S
通讯作者：
NISHIMURA, S