Umemura T, Kai S, Hasegawa R, Sai K, Kurokawa Y, Williams G M
Division of Toxicology, Division of Risk Assessment and Biological Safety Research Center, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan.
Carcinogenesis. 1999 Jun;20(6):1115-20. doi: 10.1093/carcin/20.6.1115.
To elucidate the mechanism of hepatocarcinogenesis of pentachlorophenol (PCP) in mice, critical effects related to carcinogenicity were studied in the livers of B6C3F1 male mice administered PCP at concentrations of 600 and 1200 p.p.m. in the diet for 8 weeks. Oxidative stress was assessed by measurements of 8-oxodeoxyguanosine (8-oxodG) in the liver nuclear DNA and hepatocyte cell proliferation was quantified by bromodeoxyuridine incorporation. Also, initiation and promotion were assessed in a two-stage hepatocarcinogenesis model in which one group of mice was given PCP at concentrations of 600 and 1200 p.p.m. as initiator for the first 13 weeks with subsequent administration of phenobarbital (PB) as promoter at a concentration of 500 p.p.m. in the drinking water for 29 weeks. A second group was initiated with diethylnitrosamine (DEN) at 20 p.p.m. in the drinking water for the first 13 weeks followed after a 4 week recovery interval by PCP at concentrations of 300 and 600 p.p.m. in the diet for 25 weeks. Significant elevations in 8-oxodG levels and cell proliferation were observed in a dose-dependent manner. Incidences and multiplicities of hepatocellular tumors in mice treated with PCP after DEN initiation were increased compared with those in mice given initiation only. In contrast, in mice given PCP as initiator followed by PB no enhancement of neoplastic lesions occurred. These findings are interpreted to demonstrate that PCP exerts a promoting action, but not an initiating effect on liver carcinogenesis and that the promoting action is related to oxidative stress and compensatory hepatocellular proliferation.
为阐明五氯苯酚（PCP）诱导小鼠肝癌发生的机制，研究了B6C3F1雄性小鼠肝脏中与致癌性相关的关键效应。将PCP以600和1200 ppm的浓度添加到饲料中，喂养小鼠8周。通过测量肝细胞核DNA中的8-氧代脱氧鸟苷（8-oxodG）评估氧化应激，并通过溴脱氧尿苷掺入对肝细胞增殖进行定量。此外，在两阶段肝癌发生模型中评估启动和促进作用，一组小鼠在最初13周给予600和1200 ppm浓度的PCP作为启动剂，随后以500 ppm的浓度在饮用水中给予苯巴比妥（PB）作为促进剂，持续29周。第二组在最初13周于饮用水中给予20 ppm的二乙基亚硝胺（DEN）作为启动剂，经过4周的恢复期后，在接下来的25周于饲料中给予300和600 ppm浓度的PCP。观察到8-oxodG水平和细胞增殖呈剂量依赖性显著升高。与仅给予启动剂的小鼠相比，DEN启动后给予PCP处理的小鼠肝细胞肿瘤的发生率和数量增加。相反，以PCP作为启动剂随后给予PB的小鼠中，肿瘤性病变未增强。这些结果表明，PCP对肝癌发生具有促进作用，但无启动作用，且促进作用与氧化应激和代偿性肝细胞增殖有关。
