Yan Y, Higashi K, Yamamura K, Fukamachi Y, Abe T, Gotoh S, Sugiura T, Hirano T, Higashi T, Ichiba M
Department of Biochemistry, School of Medicine, University of Occupational and Environmental Health, Fukuoka.
Jpn J Cancer Res. 1998 Aug;89(8):806-13. doi: 10.1111/j.1349-7006.1998.tb00632.x.
Carcinogen-resistant inbred DRH rats developed from the Donryu strain showed a remarkably low incidence of liver tumors when they were fed diets containing hepatocarcinogens such as 3'-methyl-4-dimethylaminoazobenzene (3'-Me-DAB). In this work, we examined various characteristics of male DRH and Donryu rats during 3'-Me-DAB administration for 8 weeks. 32P-Postlabeling analysis showed that essentially similar levels of DNA-adducts were generated by the metabolites of 3'-Me-DAB in the livers of these two strains of rats at several time points. However, both GADD45 (growth arrest and DNA damage-inducible) and O6-methylguanine methyltransferase (putatively DNA damage-inducible) mRNA levels were increased significantly in Donryu rat livers, but were increased to a lesser extent in DRH rats. [3H]Thymidine incorporation into hepatic DNA began to increase around 10 to 20 days after the start of 3'-Me-DAB administration in Donryu rats probably due to DNA repair, while no significant change occurred in DRH rats under the same conditions. Furthermore, inductions of heme oxygenase (due to degradation of heme-proteins) and hepatocyte growth factor (HGF; cell death and regeneration of hepatocytes) mRNAs were greater in Donryu rat livers than those of DRH, suggesting that the former were more sensitive to cytotoxic effects of 3'-Me-DAB than the latter. Another remarkable difference observed between these two strains was the significant induction of cytochrome P-450 2E1 mRNA in Donryu rat livers; this may contribute to the generation of reactive oxygen intermediates. Finally, increases of glutathione S-transferase (P-form) and gamma-glutamyltranspeptidase mRNAs as marker enzymes of preneoplastic changes of hepatocytes were clearly seen only in Donryu rat livers at 6 to 8 weeks after the start of 3'-Me-DAB administration. These results indicate that the different susceptibility to hepatocarcinogenesis between these two strains of rats may arise from events other than the DNA adduct formation.
从东京大鼠品系培育出的抗致癌物近交系DRH大鼠，在喂食含有3'-甲基-4-二甲基氨基偶氮苯（3'-Me-DAB）等肝癌致癌物的饲料时，肝脏肿瘤的发生率极低。在这项研究中，我们检测了雄性DRH大鼠和东京大鼠在给予3'-Me-DAB 8周期间的各种特征。32P后标记分析表明，在几个时间点，这两种品系大鼠肝脏中3'-Me-DAB的代谢产物产生的DNA加合物水平基本相似。然而，生长停滞和DNA损伤诱导基因（GADD45）和O6-甲基鸟嘌呤甲基转移酶（推测为DNA损伤诱导基因）的mRNA水平在东京大鼠肝脏中显著升高，但在DRH大鼠中升高程度较小。在东京大鼠中，[3H]胸腺嘧啶掺入肝DNA在3'-Me-DAB给药开始后约10至20天开始增加，这可能归因于DNA修复，而在相同条件下DRH大鼠未发生显著变化。此外，东京大鼠肝脏中血红素加氧酶（由于血红素蛋白降解）和肝细胞生长因子（HGF；肝细胞死亡和再生）mRNA的诱导程度高于DRH大鼠，这表明前者对3'-Me-DAB的细胞毒性作用比后者更敏感。这两个品系之间观察到的另一个显著差异是东京大鼠肝脏中细胞色素P-450 2E1 mRNA的显著诱导；这可能有助于活性氧中间体的产生。最后，仅在3'-Me-DAB给药开始后6至8周的东京大鼠肝脏中，明显观察到谷胱甘肽S-转移酶（P型）和γ-谷氨酰转肽酶mRNA作为肝细胞癌前变化的标记酶增加。这些结果表明，这两种品系大鼠对肝癌发生的不同易感性可能源于DNA加合物形成以外的事件。
