Yager J D, Potter V R
Cancer Res. 1975 May;35(5):1225-34.
The objective of the present study was to define early biochemical changes occuring in livers of rats that were fed various chemical carcinogens. Rats were subjected to partial hepatectomy and subsequently given multiple injections of radioactive thymidine to prelabel DNA in their liver. Following a 4-week recovery period the rats were placed on either basal diets or diets containing either 0.05% 3'-methyl-4-dimethylaminoazobenzene (3'-MeDAB), 0.028% 2-acetylaminofluorene, or 0.05% 2-methyl-4-dimethylaminoazobenzene for various periods. After 5 weeks 3'-MeDAB had caused a dose-dependent loss of prelabeled DNA demonstrating the cytotoxicity of this carcinogen. The comparatively noncarcinogenic 2-methyl-4-dimethylaminoazobenzene caused only a small loss of prelabeled DNA. In contrast, the hepatocarcinogen 2-acetylaminofluorene did not cause a loss of prelabeled DNA, demonstrating its low cytotoxicity. Autoradiography and histology revealed that the loss of prelabeled DNA in livers of rats fed 3'-MeDAB was largely due to parenchymal cell death. Experiments designed to separate liver regenerative hyperplasia from neoplastic hyperplasia revealed the presence of both an early and a delayed elevation of thymidine incorporation into liver DNA in rats fed 0.05% 3'-MeDAB. An "early" elevation of incorporation occurred during and shortly after 3'-MeDAB feeding, and a "delayed" elevation of incorporation occurred some weeks after the dye was discontinued. Autoradiography revealed that parenchymal cells were largely responsible for the increased incorporation. Feeding of 2-methyl-4-dimethylaminoazobenzene depressed thymidine incorproation. A direct comparison of the effects of isomolar levels of 3'-MeDAB and 2-acetylaminogluorene on hepatic hyperplasia indicated that both carcinogens caused comparable increases in thymidine incorporation, which returned to control levels upon feeding of carcinogen-free diet. The differences and similarities between the responses to the three compounds are discussed and considered with regard to initiation and promotion of hepatoma formation.
本研究的目的是确定喂食各种化学致癌物的大鼠肝脏中早期发生的生化变化。大鼠接受部分肝切除术，随后多次注射放射性胸苷以预先标记其肝脏中的DNA。经过4周的恢复期后，将大鼠置于基础饮食或含有0.05% 3'-甲基-4-二甲基氨基偶氮苯（3'-MeDAB）、0.028% 2-乙酰氨基芴或0.05% 2-甲基-4-二甲基氨基偶氮苯的饮食中不同时间段。5周后，3'-MeDAB导致预先标记的DNA呈剂量依赖性损失，证明了这种致癌物的细胞毒性。相对无致癌性的2-甲基-4-二甲基氨基偶氮苯仅导致预先标记的DNA少量损失。相比之下，肝癌致癌物2-乙酰氨基芴并未导致预先标记的DNA损失，表明其细胞毒性较低。放射自显影和组织学显示，喂食3'-MeDAB的大鼠肝脏中预先标记的DNA损失主要是由于实质细胞死亡。旨在区分肝脏再生性增生和肿瘤性增生的实验表明，喂食0.05% 3'-MeDAB的大鼠肝脏DNA中胸苷掺入量存在早期和延迟升高。“早期”掺入升高发生在3'-MeDAB喂食期间及之后不久，“延迟”掺入升高发生在染料停用几周后。放射自显影显示实质细胞是掺入增加的主要原因。喂食2-甲基-4-二甲基氨基偶氮苯会降低胸苷掺入。对等摩尔水平的3'-MeDAB和2-乙酰氨基芴对肝脏增生的影响进行直接比较表明，两种致癌物导致胸苷掺入量有相当程度的增加，在喂食无致癌物饮食后恢复到对照水平。讨论并考虑了对这三种化合物反应的差异和相似性与肝癌形成的启动和促进的关系。
