EARLY EVENTS IN CHEMICALLY INDUCED RAT HEPATOCARCINOGENESIS

化学诱导的大鼠肝癌的早期事件

• 批准号: 3939657
• 负责人: P J WIRTH
• 金额: --
• 依托单位: DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3939657
• 关键词: chemical carcinogen; chemical carcinogenesis; cobalt; cytoplasm; disease /disorder model; gel electrophoresis; gene expression; glutathione transferase; high performance liquid chromatography; lead; liver cells; liver metabolism; liver neoplasms; methylcholanthrene; neoplasm /cancer genetics; oncoproteins; phenobarbital; preneoplastic state; radiotracer; tissue /cell culture

This project was initiated to study the sequence of events during chemically induced neoplasia using the rodent hepatoma model in combination with quantitative two-dimensional gel electrophoresis (2D-PAGE). Hyperplastic nodules (HN) were generated in male F-344 rats using the resistant hepatocyte model. Six months after initiation animals bearing HN and untreated control rats were treated with the following compounds known to modulate liver enzymes and proteins: lead nitrate (LN), cobaltheme (CoH), 3-methylcholanthrene (3MC), and phenobarbital (PB). In control animals LN, CoH, 3MC, and PB treatment all resulted in a two- to tenfold increase in the expression of the Yc subunit of glutathione-S-transferase (GST). PB also increased the Yb and Ya subunits fivefold each. LN also increased the expression of a polypeptide tentatively identified as the Yp subunit of the placetal form of GST-P. Neither CoH, 3MC, nor PB had any effect on the expression of this polypeptide. Polypeptide 8, composed of 5 isoelectric point variants (6.00-6.60/66,000) was increased two-to threefold in HN from untreated animals and was similarly increased in normal liver following treatment with each of the four modulators. The order of potency was: LN greater than CoH greater than PB = 3MC. Polypeptides 6 (6.60/21,000) and 7 (6.40/16,000) which were expressed at relatively high levels in normal liver (0.5-0.6% of the total integrated density on each gel) were reduced three- to fivefold in HN. Following treatment of normal liver with either LN, 3MC, or CoH, polypeptides 6 and 7 were reduced to 0.1-0.2% and 0.2-0.3%, respectively. Polypeptide 3 (5.90/38,000) which is markedly reduced in HN is similarly decreased in normal liver by LN, PB, and CoH. 2D-PAGE of microsomal polypeptides failed to reveal any common polypeptide changes between HN and modulator-treated normal liver, although numerous qualitative and quantitative differences specific to each modulator were observed.

该项目的启动是为了研究 使用啮齿动物肝癌模型， 结合定量二维凝胶 电泳（2D-PAGE）。 增生性结节（HN） 使用抗性肝细胞在雄性F-344大鼠中产生 模型 启动后6个月，携带HN的动物和 未处理的对照大鼠用以下药物处理 已知调节肝酶和蛋白质的化合物：铅 硝酸根（LN）、四氢钴（CoH）、3-甲基胆蒽（3 MC）、 和苯巴比妥（PB）。 在对照动物LN、CoH、3 MC和 PB处理都导致了两到十倍的增加， 谷胱甘肽-S-转移酶（GST）的Yc亚基的表达。 PB也增加了Yb和Ya亚基各5倍。 LN也 增加了一种多肽的表达， 作为GST-P的占位形式的Yp亚基。CoH， 3 MC、PB对该基因的表达无影响， 多肽。 多肽8，由5个等电点组成 在HN中，变异（6.00-6.60/66，000）增加了2 - 3倍 未处理的动物中， 在用四种调节剂中的每一种处理后的肝脏中。 的 效力顺序为：LN大于CoH大于PB = 3MC。 多肽6（6.60/21，000）和7（6.40/16，000）， 在正常肝组织中表达水平较高（0.5-0.6%） 在每个凝胶上的总积分密度）减少了三个- 在HN中为5倍。 在用以下药物治疗正常肝脏后， LN、3 MC或CoH，多肽6和7被还原为 0.1-0.2%和0.2- 0.3%。 多肽3（5.90/38，000） 在HN中显著降低的，在正常 肝脏LN、PB和CoH。 微粒体多肽的2D-PAGE 未能揭示HN之间任何共同的多肽变化 和调节剂处理的正常肝脏，尽管许多 每一个具体的质量和数量差异 调制器进行了观察。