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。

• 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

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)是第一个被发现的啮齿动物肝脏肿瘤促进剂，其致癌的两阶段或启动-促进概念。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，尽管它是非遗传毒性的。然而，重要的是，人们也知道，在小鼠中，PB有时对由强大的致癌物二乙基亚硝胺(DEN)引发的肝癌具有很强的抑制作用。例如，虽然PB促进了成年后用DEN启动的B6C3F1小鼠的肝脏肿瘤的发展，但它强烈地抑制了在婴儿时期使用DEN启动的相同小鼠的肝癌发生。在将实验动物的实验风险数据外推到人类病例时，PB在小鼠身上的这种矛盾的结果将提出一个严重的问题。在这项研究中，我提供了证据，考虑到启动病变的质量多样性及其对苯巴比妥促进的不同反应，PB在肝癌发生中的矛盾作用可以得到解决。因此，我建议从启动的质量异质性的角度重新考虑经典的两阶段概念。我还发现，PB在与c-myc过表达协同作用的培养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因子。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，其分子机制显然需要进一步分析。

项目成果

Osanai, M.: "Phenobarbital causes apoptosis in conditionally immortalized mouse hepatocytes depending on deregulated c-myc expression : characeterization of an unexpected effect." Cancer Research. 57. 2896-2903 (1997)

Osanai, M.：“苯巴比妥根据 c-myc 表达失调导致条件永生化小鼠肝细胞凋亡：意外效应的表征。”

Karasaki,H.: "Roles of the Pasl and Par2 genes in determination of the unique,intermediate susceptibility of BALB/cByJ mice to urethane-induction of lung carcinogenesis:differential effects on tumor multiplicity,size and Kras2 mutations." Oncogene. 15. 18

Karasaki, H.：“Pasl 和 Par2 基因在确定 BALB/cByJ 小鼠对氨基甲酸乙酯诱导肺癌的独特中间易感性中的作用：对肿瘤多重性、大小和 Kras2 突变的不同影响。”

Lee, G.-H., Ooasa, T., and Osanai, M.: "Mechanism of the paradoxical, inhibitory effect of phenobarbital on hepatocarcinogenesis initiated infant B6C3F_1 mice with diethylnitrosamine." Cancer Res.58. 1665-1669 (1998)

Lee, G.-H.、Ooasa, T. 和 Osanai, M.：“苯巴比妥对使用二乙基亚硝胺引发的婴儿 B6C3F_1 小鼠肝癌发生的矛盾抑制作用机制。”

Osanai,M.: "Phenobarbital causes apoptosis in conditionally immortalized mouse hepatocytes depending on deregulated c-myc expression:characterization of an unexpected effect." Cancer Res.57. 2896-2903 (1997)

Osanai,M.：“苯巴比妥根据 c-myc 表达失调导致条件永生化小鼠肝细胞凋亡：意外效应的表征。”