Degawa M, Hishinuma T, Yoshida H, Hashimoto Y
Department of Hygienic Chemistry, Tohoku University, Sendai, Japan.
Carcinogenesis. 1987 Dec;8(12):1913-8. doi: 10.1093/carcin/8.12.1913.
Both sexes of BALB/c X DBA/2 F1 mice and F344 rats were treated for 1 week with a diet containing 0.02% of hepatocarcinogenic tryptophan pyrolysate component (Trp P-1 or Trp P-2), and changes in the carcinogen activation enzyme activity in various organs were examined comparatively using a mutation test with Salmonella typhimurium TA98 as a tester bacterium. Hepatic enzymes from untreated mice and rats showed a definite catalytic activity for mutagenic activations of Trp P-1 and Trp P-2, whereas the activities of other organs--such as lung, kidney, small intestine and colon--were undetectable or very low. In both mice and rats either the Trp P-1 or Trp P-2 feeding resulted in induction of cytochrome P-450 isozyme(s), which could mediate in the liver but not in other organs the mutagenic activation of the carcinogen itself. As to the sex difference, the induction of the activation enzyme(s) was greater in the female animals than in the males. Species difference in the activity of hepatic enzymes catalyzing the Trp P-1 and Trp P-2 mutageneses was also observed in animals treated with the basal diet; the activity was higher in mice than in the sex-matched rats (Trp P-1, approximately 1.5-fold; Trp P-2, approximately 7-fold). When diet containing Trp P-1 or Trp P-2 was fed for 1 week, the activity of the rat liver for Trp P-1 mutagenesis was of a level similar to that of the sex-matched mice, but for Trp P-2 mutagenesis it was less than half that in the mice. The induced hepatic enzymes in mice and rats were suggested to be 3-methylcholanthrene-inducible cytochrome P-448 isozymes as determined by mutation tests with Trp P-1, Trp P-2 and two other substrates and by immunochemical analyses of rat hepatic cytochrome P-450 using monoclonal antibodies against rat cytochrome P-448 isozymes. These results indicate that a form of cytochrome P-450 responsible for activation of Trp P-1 and Trp P-2 is inducible by dietary treatment of mice or rats with these carcinogens and that the amount of the cytochrome P-450, including resident and induced forms, is related to the species, sex and organ differences in their carcinogenic susceptibility to these chemicals.
给BALB/c X DBA/2 F1小鼠和F344大鼠的雌雄两性喂食含0.02%致癌性色氨酸热解产物成分（Trp P - 1或Trp P - 2）的饲料1周，以鼠伤寒沙门氏菌TA98作为测试菌，通过突变试验比较检测各器官中致癌物激活酶活性的变化。未处理的小鼠和大鼠的肝酶对Trp P - 1和Trp P - 2的诱变激活表现出一定的催化活性，而其他器官如肺、肾、小肠和结肠的活性检测不到或非常低。在小鼠和大鼠中，喂食Trp P - 1或Trp P - 2均可诱导细胞色素P - 450同工酶，其可在肝脏中介导致癌物自身的诱变激活，但在其他器官中则不能。关于性别差异，雌性动物中激活酶的诱导程度高于雄性。在用基础饲料处理的动物中也观察到了催化Trp P - 1和Trp P - 2诱变的肝酶活性的物种差异；小鼠中的活性高于性别匹配的大鼠（Trp P - 1约为1.5倍；Trp P - 2约为7倍）。当喂食含Trp P - 1或Trp P - 2的饲料1周时，大鼠肝脏对Trp P - 1诱变的活性与性别匹配的小鼠相似，但对Trp P - 2诱变的活性不到小鼠的一半。通过用Trp P - 1、Trp P - 2和其他两种底物进行突变试验以及使用抗大鼠细胞色素P - 448同工酶的单克隆抗体对大鼠肝细胞色素P - 450进行免疫化学分析，表明小鼠和大鼠中诱导的肝酶为3 - 甲基胆蒽诱导的细胞色素P - 448同工酶。这些结果表明，负责激活Trp P - 1和Trp P - 2的细胞色素P - 450形式可通过用这些致癌物对小鼠或大鼠进行饮食处理来诱导，并且细胞色素P - 450的量，包括固有形式和诱导形式，与它们对这些化学物质的致癌易感性的物种、性别和器官差异有关。
