肝细胞间隙连接通讯促进剂对小鼠肝肿瘤发生的抑制作用

目的 通过活体动物实验，探讨肝组织肿瘤发生机制是否与该组织细胞间隙连接通讯（GJIC）受阻有关，促进GJIC的药物对肿瘤发生是否具有对抗作用。方法 初生雄性ICR小鼠60只。40只腹腔注射二乙基亚硝胺（DEN）诱发肝肿瘤（肝肿瘤模型），20只注射等体积溶剂（三辛酸甘油）作为对照组。断乳后，肝肿瘤模型20只每日皮下注射异丙肾上腺素（IP）0．75μg／g＋咖啡因（CAF）1．5μg/g（DEN-IP＋CAF组），另20只注射等体积生理盐水（单纯DEN组）。所有动物均喂饲高蛋白低碳水化合物半精制饲料。采用羧基荧光素（CoF）细胞问转移法在新鲜离体的完整肝叶上测定肝GJIC能力，每组测定8只，其余在13月龄时处死，检测肝肿瘤。结果 单纯DEN组从断乳后不到半月开始至半年之后，肝GJIC能力降至正常水平的1／3（P〈0．001）并持续低水平，此时正在长大的结节出现在肝表面。DEN-IP＋CAF组，至少在断乳后头4．5月内肝GJIC能力呈现正常水平，到13月龄时与单纯DEN组相比，肝结节总体积减小98％（P〈0．001），肝细胞腺瘤发生率减少50％（P〈0．01）。对照组肝脏无异常发现。结论 在DEN诱发的小鼠肝肿瘤发生过程中，肝GJIC的早期下降是一关键性病理生理变化：促进GJIC的药物可对抗这种变化。对肝肿瘤的发生有抑制作用。

Inhibition of Mouse Liver Tumorigenesis by Hepatic Gap Junctional Communication Promoter

Objective To study the effect of inhibition of gap junctional intercellular communication(GJIC) promoter in tumorigenesis and the anti-oncogenesis effect of the GJIC promoter. Methods 60 new born male ICR mice were each given a single ip.injection of diethylnitrosamine(DEN) for liver tumor induction(40 mice) or of the solvent without DEN for control(20 mice). After weaning, half of the DEN-injected mice received daily sc.isoproterenol plus caffeine for liver GJIC activation and all the animals were fed a high protein low carbohydrate feed. Liver GJIC capacity was determined in 8 mice of each group by carboxyfluorescein cell-to-cell transfer assay performed on fresh intact liver lobes. Liver tumorigenesis was analysed with 12 mice of each group at the age of 13 months. Results In the DEN group liver GJIC decreased to below 1/3 of the control level(P<0.001) within half month after weaning and remainded low at least to half year later until growing nodules had emerged on the liver surfaces. In DEN-isoproterenol+caffeine group the liver GJIC appeared normal for at least 4.5 months after weaning, resulting 98% reduction in the mean total node volume per liver(P<0.001), 50% reduction in the incidence of hepatocellular adenomas(P<0.01), as compared with the DEN group. Control mice showed no liver abnormality. Conclusion Early inhibition of hepatic GJIC is critical in induction of DEN mouse liver carcinogenesis; disinhibition by pharmacological means can suppress this process.