Paradoxical effects of phenobarbital on hepatocarcinogenesis and hepatocytic apoptosis.

苯巴比妥对肝癌发生和肝细胞凋亡的矛盾作用。

基本信息

批准号：
09670213
负责人：
LEE Gang-Hong
金额：
$ 1.66万
依托单位：
Asahikawa Medical College
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1998
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09670213/
关键词：
Phenobarbital Chemical hepatocarcinogenesis Inhibition Hepatocyte Apoptosis Mouse Bcl-2 Paradox 肝発癌増殖

项目摘要

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.

苯巴比妥 (PB) 是第一个发现的啮齿类动物肝脏肿瘤促进剂，就致癌作用的两阶段或起始促进概念而言。在使用基因毒性致癌剂的大鼠和小鼠中，苯巴比妥已被证明可以使肝细胞肿瘤的数量增加约 5 倍，尽管它没有基因毒性。然而，重要的是，我们还知道，在小鼠中，PB 偶尔会表现出强烈的抑制作用。对强效致癌物二乙基亚硝胺 (DEN) 引发的肝癌发生的影响。例如，虽然 PB 促进了成年后接受 DEN 治疗的 B6C3F1 小鼠肝脏肿瘤的发展，但它强烈抑制了在婴儿期接受 DEN 治疗的同一小鼠的肝癌发生。当将实验动物的实验风险数据外推到人类病例时，PB 治疗小鼠的这种矛盾结果会引发严重问题。在这项研究中，我提供的证据表明，考虑到起始病变的质量多样性，PB 对肝癌发生的矛盾作用可以得到解决以及他们对苯巴比妥促销的不同反应。因此，我建议应该从起始的定性异质性角度重新考虑经典的两阶段概念。我还发现，PB 在与 c-myc 过表达配合的培养物中诱导小鼠肝细胞凋亡。这是一个意想不到的现象，因为PB一直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增加10倍。因此，PB的生物学效应相当复杂，显然需要进一步分析其分子机制。