Diwan B A, Rice J M, Ohshima M, Ward J M
Carcinogenesis. 1986 Feb;7(2):215-20. doi: 10.1093/carcin/7.2.215.
Selected inbred strains of mice were compared with respect to their susceptibility to two-stage liver carcinogenesis. Five-week-old male mice of strains C57BL/6NCr (C57), C3H/HeNCrMTV- (C3H) and DBA/2NCr (DBA) were given a single i.p. injection of N-nitrosodiethylamine (DEN, 90 mg/kg body weight) or the solvent tricaprylin (10 ml/kg). Beginning 2 weeks later, half of the DEN-treated and half of the control mice were given drinking water containing 0.05% phenobarbital (PB). Ten mice from each treatment group were killed at 12, 24, 36 and 52 weeks of age (5, 17, 29 and 45 weeks exposure to PB). PB significantly increased both the number of hepatocellular foci/cm2 and the incidence of hepatocellular tumors after 17 weeks of treatment in 24-week-old DEN-initiated mice of strains C3H (0.11 +/- 0.07 versus 2.9 +/- 0.3 foci/cm2 and 20 versus 70% incidence of hepatocellular tumors) and DBA (0.09 +/- 0.09 versus 3.72 +/- 0.6 foci/cm2 and 0 versus 90% incidence of hepatocellular tumors) but was ineffective in C57 mice (0.04 +/- 0.04 versus 0.07 +/- 0.07 foci/cm2). At 36 weeks of age the incidence of liver cell tumors in mice given DEN but not PB was 10 (DBA), 10 (C57) and 50% (C3H); the incidence was increased by PB to 90% in DBA and 100% in C3H mice, but there was no increase in C57 mice. Even at 52 weeks, the low incidence of hepatocellular tumors in C57 mice given DEN only (20%) was not significantly increased by subsequent exposure to PB. Serum PB levels observed at 12, 24 and 36 weeks of age were significantly higher in DBA mice than in C57 or C3H mice. Similar results were observed in a separate study in which PB was administered in drinking water to 7-week-old male mice of these three strains for 20 days, during which period serum PB levels were measured at shorter intervals. DBA mice thus appear to be unable to metabolize PB, which itself rather than its metabolites is probably responsible for tumor-promoting effects. DBA mice were especially sensitive, while C57 mice were refractory to promotion of hepatocarcinogenesis by PB. These two strains, which differ with respect to other significant parameters for chemical carcinogenesis including inducibility for aryl hydrocarbon hydroxylase and susceptibility to promotion of hydrocarbon-initiated skin tumors by 12-O-tetradecanoylphorbol-13-acetate, thus also provide a means for analysis of the pharmacogenetics of susceptibility to hepatocellular tumor promotion.
对选定的近交系小鼠进行了关于其对二阶段肝癌发生易感性的比较。将C57BL/6NCr（C57）、C3H/HeNCrMTV-（C3H）和DBA/2NCr（DBA）品系的5周龄雄性小鼠经腹腔单次注射N-亚硝基二乙胺（DEN，90毫克/千克体重）或溶剂三辛酸甘油酯（10毫升/千克）。2周后开始，将一半经DEN处理的小鼠和一半对照小鼠给予含0.05%苯巴比妥（PB）的饮用水。每个处理组的10只小鼠在12、24、36和52周龄时处死（暴露于PB 5、17、29和45周）。在24周龄经DEN启动的C3H品系小鼠（0.11±0.07对2.9±0.3个病灶/平方厘米以及肝细胞肿瘤发生率20%对70%）和DBA品系小鼠（0.09±0.09对3.72±0.6个病灶/平方厘米以及肝细胞肿瘤发生率0对90%）中，PB在处理17周后显著增加了每平方厘米肝细胞病灶数量和肝细胞肿瘤发生率，但在C57小鼠中无效（0.04±0.04对0.07±0.07个病灶/平方厘米）。在36周龄时，给予DEN但未给予PB的小鼠中肝细胞肿瘤发生率在DBA中为10%，在C57中为10%，在C3H中为50%；PB使DBA小鼠中的发生率增加到90%，在C3H小鼠中增加到100%，但在C57小鼠中无增加。即使在52周时，仅给予DEN的C57小鼠中肝细胞肿瘤的低发生率（20%）在随后暴露于PB后也未显著增加。在12、24和36周龄时观察到的血清PB水平在DBA小鼠中显著高于C57或C3H小鼠。在另一项单独研究中观察到类似结果，其中将PB添加到这三个品系的7周龄雄性小鼠饮用水中20天，在此期间以更短间隔测量血清PB水平。因此，DBA小鼠似乎无法代谢PB，可能是PB本身而非其代谢产物具有促肿瘤作用。DBA小鼠特别敏感，而C57小鼠对PB促进肝癌发生具有抗性。这两个品系在化学致癌的其他重要参数方面存在差异，包括芳烃羟化酶的诱导性以及12-O-十四烷酰佛波醇-13-乙酸酯对烃类启动的皮肤肿瘤促进作用的易感性，因此也为分析肝细胞肿瘤促进易感性的药物遗传学提供了一种手段。
