Paradoxical effects of phenobarbital on hepatocarcinogenesis and hepatocytic apoptosis.

苯巴比妥（PB）是第一个发现的啮齿类动物肝脏肿瘤促进剂。在由遗传毒性致癌物引发的大鼠和小鼠中，苯巴比妥已被证明可使肝细胞肿瘤的数量增加约5倍，尽管其无遗传毒性。然而，重要的是，还已知在小鼠中，PB偶尔对由强效致癌物二乙基亚硝胺（DEN）引发的肝癌发生具有强烈的抑制作用。例如，虽然PB增强了成年时由DEN引发的B6 C3 F1小鼠的肝脏肿瘤的发展，但它强烈抑制了在婴儿期由DEN引发的相同小鼠的肝癌发生。PB治疗小鼠的这种矛盾的结果将提出一个严重的问题时，外推的实验室动物的实验风险数据，以人类cases.In这项研究中，我提供的证据表明，PB对肝癌发生的矛盾行动可以解决考虑质量多样性的启动病变和他们的差异反应苯巴比妥促进。因此，我建议，经典的两个阶段的概念，应重新考虑在定性的异质性initiation.I还发现，PB诱导细胞凋亡的小鼠肝细胞在文化合作与c-myc过表达。这是一个意想不到的现象，因为PB被认为是肝细胞凋亡的抑制剂。PB诱导的细胞凋亡伴随着凋亡蛋白Bax的10倍增加，因此PB的生物学效应是相当复杂的，其分子机制有待进一步研究。

Phenobarbital (PB) is the first discovered tumor promoter for rodent livers in terms of the two-stage or initiation-promotion concept of carcinogenesis. In rats and mice initiated with genotoxic carcinogens, phenobarbital has been shown to increase the number of hepatocellular tumors by approximately 5-fold despite its non-genotoxicity.Importantly, however, it has been also known that, in mice, PB occasionally exhibits strong inhibitory effects on hepatocarcinogenesis initiated with a potent carcinogen, diethylnitrosamine (DEN). For example, while PB enhances development of liver tumors in B6C3F1 mice initiated with DEN as adults, it strongly inhibits hepatocarcinogenesis in the same mice initiated with DEN in their infancy. Such paradoxical outcomes of PB treatment in mice would raise a serious issue when extrapolating the experimental risk data of laboratory animals to human cases.In this study, I provided evidence that the paradoxical actions of PB on hepatocarcinogenesis can be resolved considering qualitative diversity of initiated lesions and their differential responses to phenobarbital promotion. Thus, I propose that the classical two-stage concept should be reconsidered in terms of qualitative heterogeneity of initiation.I also found that PB induces apoptosis in mouse hepatocytes in culture cooperating with c-myc overexpression. This is an unexpected phenomenon, because PB has been regarded as an inhibitor on hepatocytic apoptosis. The PB-induced apoptosis was accompanied by a 10-fold increase in Bax, an apoptotic protein.Consequently, biological effects of PB are quite complicated and clearly need further analysis on their molecular mechanisms.