Yano M, Higashi T, Kano S, Tateishi N, Kido Y, Mori T, Higashi K, Sakamoto Y
Department of Oncology, Osaka University Medical School, Japan.
Cancer Res. 1989 Oct 1;49(19):5352-7.
We have developed a new strain of rats (resistant rat) which exhibit resistance against the carcinogenic action of several carcinogenic compounds. In the present study, we compared the ability of resistant rat liver to activate 3'-methyl-4-dimethylaminoazobenzene and 2-acetylaminofluorene to highly reactive metabolites, which can covalently bind to DNA, with that of carcinogen-sensitive parent strain rats (sensitive rat), using in vitro DNA binding assay. The covalent binding of these carcinogens to calf thymus DNA, catalyzed by the hepatic 9000 x g supernatant fraction from resistant rats pretreated with 3-methylcholanthrene, was about one-half of that catalyzed by the 9000 x g supernatant from sensitive rats which had received the same treatment. These results suggest that the ability of resistant rat liver to activate the carcinogens decreases compared to sensitive rat liver. Further experiments revealed that this decreased activation of the carcinogens in resistant rat livers is due to a low inducibility of 3-methylcholanthrene-inducible forms of cytochrome P-450 mRNA. The hepatic cytosolic Ah receptor concentrations in resistant rats were shown to be significantly lower than those of sensitive rats. Scatchard plot analysis demonstrated, however, that there is no significant difference between the affinity of Ah receptors for 2,3,7,8-tetrachlorodibenzo-p-dioxin in these two strains. These data implicate that the hepatic Ah receptor level may be an important factor in determining carcinogen sensitivity in rats.
我们培育出了一种新型大鼠（抗性大鼠），它对几种致癌化合物的致癌作用具有抗性。在本研究中，我们使用体外DNA结合试验，比较了抗性大鼠肝脏与致癌物敏感的亲代品系大鼠（敏感大鼠）将3'-甲基-4-二甲基氨基偶氮苯和2-乙酰氨基芴激活为高反应性代谢产物（可与DNA共价结合）的能力。用3-甲基胆蒽预处理的抗性大鼠肝脏9000×g上清液部分催化这些致癌物与小牛胸腺DNA的共价结合，约为接受相同处理的敏感大鼠9000×g上清液催化量的一半。这些结果表明，与敏感大鼠肝脏相比，抗性大鼠肝脏激活致癌物的能力降低。进一步的实验表明，抗性大鼠肝脏中致癌物激活能力的降低是由于细胞色素P-450 mRNA的3-甲基胆蒽诱导型的低诱导性。结果显示，抗性大鼠肝脏胞质溶胶中的芳烃受体浓度显著低于敏感大鼠。然而，Scatchard作图分析表明，这两个品系中芳烃受体对2,3,7,8-四氯二苯并对二恶英的亲和力没有显著差异。这些数据表明，肝脏芳烃受体水平可能是决定大鼠致癌物敏感性的一个重要因素。
