Study on the mechanism of the chemical carcinogenesis of cirrhotic liver

肝硬化肝化学致癌机制研究

• 批准号: 03670634
• 负责人: MIYAZAKI Kohji
• 金额: $ 1.28万
• 依托单位: Saga Medical School
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1991
• 资助国家: 日本
• 起止时间: 1991 至 1992
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-03670634/
• 关键词: Liver cirrhosis; Chemical carcinogenesis; DNA injury; Reduced glutathione; Cytochrome P-450; Alkaline elution; チトクロ-ムPー450

The effects of reduced glutathione (GSH) and ethanol on aflatoxin B_1 AFB_1)-induced DNA single strand breaks and AFB_1-DNA adduct formation were studied in primary cultured hepatocytes. Buthionine sulphoximine (BSO) decreased intracellular GSH to 13% of those of control levels, increased DNA fragmentation of AFB_1-treated hepatocytes by over 17% of those without BSO. Thus a decrease in hepatocyte GSH levels increased AFB_1-induced DNA damage. Although ethanol in itself did not induce DNA damage, a combination of BSO and ethanol increased the percentage by over 23% of that with BSO only. BSO significantly enhanced the formation of [^3H]AFB_1-DNA adducts and ethanol further increased it in the presence of BSO, whereas ethanol did not affect the amount of GSH, total cytochrome P-450, glutathione S-transferase and epoxide hydrolase in cultured hepatocytes. However, GSH-depleted rat hepatocytes exposed to ethanol significantly increased the level of cytochrome P450IIIA, which activates AFB_1. The enhancing effects of ethanol in the presence of BSO are probably due to the induction of this enzyme in rat hepatocytes.

在原代培养的肝细胞中研究了还原性谷胱甘肽（GSH）和乙醇对黄曲霉毒素B_1 AFB_1）诱导的DNA单链断裂和AFB_1-DNA加合物形成的影响。丁香硫胺（BSO）将细胞内GSH降低至对照水平的13％，AFB_1处理的肝细胞的DNA碎片增加了没有BSO的17％以上。因此，肝细胞GSH水平的降低增加了AFB_1诱导的DNA损伤。尽管乙醇本身并未诱导DNA损伤，但仅使用BSO，BSO和乙醇的组合将超过23％的百分比增加了。 BSO显着增强了[^3H] AFB_1-DNA加合物和乙醇的形成，而在BSO的存在下，它进一步增加了它，而乙醇并不影响培养的Hepatocytes中GSH，总细胞色素P-450，谷胱甘肽S-转移酶和环氧化物水解酶的数量。然而，暴露于乙醇的GSH耗尽的大鼠肝细胞显着提高了激活AFB_1的细胞色素P450IIIA的水平。在BSO存在下乙醇的增强作用可能是由于该酶在大鼠肝细胞中诱导的效果。

项目成果

堤 宣翁,宮崎 耕治,他: "アルコール性肝硬変における化学発癌の可能性とその機序(第II法)" 消化器癌の発生と進展. 4. 375-377 (1992)

Nobuo Tsutsumi、Koji Miyazaki 等：“酒精性肝硬化中化学致癌的可能性和机制（方法 II）” 胃肠癌的发生和进展（1992 年）。

堤 宣翁: "化学発癌物質スクリーニングモデルとしての肝細胞/in situニックトランスレーション法とその応用" 肝臓. 33. 161-166 (1992)

Nobuo Tsutsumi：“肝细胞作为化学致癌物筛选模型/原位切口平移方法及其应用”，Liver. 33. 161-166 (1992)。

宮崎 耕治: "胆道粘膜上皮細胞の初代培養-胆道癌化学発癌物質検出のためのスクリーニング法" 消化器癌. 1. 521-524 (1991)

Koji Miyazaki：“胆道粘膜上皮细胞的原代培养-检测胆道癌化学致癌物的筛选方法”胃肠癌。1. 521-524 (1991)

宮崎 耕治: "肝・胆道癌の研究における細胞培養" 組織培養. 17. 26-29 (1991)

Koji Miyazaki：“肝癌和胆道癌研究中的细胞培养”《组织培养》17. 26-29 (1991)。

堤 宣翁: "アルコール性肝硬変における化学発癌の可能性とその機序" 消化器癌の発生と進展. 3. 381-384 (1991)

Nobuo Tsutsumi：“酒精性肝硬化化学致癌的可能性和机制”胃肠癌的发生和进展（1991）。