Buchmann A, Kuhlmann W, Schwarz M, Kunz W, Wolf C R, Moll E, Friedberg T, Oesch F
Carcinogenesis. 1985 Apr;6(4):513-21. doi: 10.1093/carcin/6.4.513.
Nitrosamine-induced hepatocarcinogenesis has been used to investigate the regulation and expression of different drug-metabolizing enzymes in preneoplastic and neoplastic lesions in the female Wistar rat. The enzymes investigated were two phenobarbital-inducible cytochrome P-450 (cyt. P-450) isoenzymes (PB1 and PB2, mol. wt. 52 000 and 53 500, respectively), two 3-methylcholanthrene-inducible forms (MC1 and MC2, mol. wt. 54 500 and 57 000, respectively), NADPH-cytochrome P-450 reductase, the cytosolic glutathione transferases (GSTs) B and C and the microsomal epoxide hydrolase with broad substrate specificity (mEHb). Carcinogen-induced lesions were identified by use of the known markers of hepatocarcinogenesis adenosinetriphosphatase and gamma-glutamyl transpeptidase. While the GSTs and mEHb were increased in all preneoplastic and neoplastic lesions, the levels of the individual cyt. P-450 isoenzymes were characteristically different from each other. In many of the early ATPase deficient islets PB1 was elevated, whereas the content of the other cyt. P-450 forms and NADPH-cytochrome P-450 reductase was either unchanged or slightly lowered. At later stages of hepatocarcinogenesis PB1 returned to the levels of the surrounding tissue, while the other cyt. P-450 isoenzymes were decreased, the most prominent reduction being found in MC1. In neoplastic nodules all the cyt. P-450s and NADPH-cyt. P-450 reductase were diminished, some of them dramatically. These findings indicate that in spite of a common response of groups of P-450s to inducing agents, individual P-450 isoenzymes are also regulated separately. Moreover, the constant elevation of mEHb and GSTs in all lesions investigated in this study demonstrates that these enzymes, which are largely involved in deactivation, are regulated in a different fashion from the predominantly carcinogen-activating monooxygenases. The observed differences in enzyme pattern may provide a useful method for subdividing and categorizing preneoplastic and neoplastic lesions.
亚硝胺诱导的肝癌发生已被用于研究雌性Wistar大鼠癌前病变和肿瘤病变中不同药物代谢酶的调节和表达。所研究的酶包括两种苯巴比妥诱导的细胞色素P - 450（cyt. P - 450）同工酶（PB1和PB2，分子量分别为52000和53500）、两种3 - 甲基胆蒽诱导形式（MC1和MC2，分子量分别为54500和57000）、NADPH - 细胞色素P - 450还原酶、胞质谷胱甘肽转移酶（GSTs）B和C以及具有广泛底物特异性的微粒体环氧化物水解酶（mEHb）。通过使用肝癌发生的已知标志物三磷酸腺苷酶和γ - 谷氨酰转肽酶来识别致癌物诱导的病变。虽然GSTs和mEHb在所有癌前病变和肿瘤病变中均增加，但各个cyt. P - 450同工酶的水平彼此特征性不同。在许多早期ATP酶缺乏的胰岛中，PB1升高，而其他cyt. P - 450形式和NADPH - 细胞色素P - 450还原酶的含量要么不变，要么略有降低。在肝癌发生的后期，PB1恢复到周围组织的水平，而其他cyt. P - 450同工酶减少，MC1减少最为明显。在肿瘤结节中，所有的cyt. P - 450和NADPH - cyt. P - 450还原酶都减少，其中一些显著减少。这些发现表明，尽管一组P - 450对诱导剂有共同反应，但各个P - 450同工酶也分别受到调节。此外，本研究中所有研究病变中mEHb和GSTs的持续升高表明，这些主要参与失活的酶与主要参与致癌物激活的单加氧酶的调节方式不同。观察到的酶模式差异可能为癌前病变和肿瘤病变的细分和分类提供一种有用的方法。
