Hlavica P
Walther Straub-Institut für Pharmakologie und Toxikologie der Universität, München, Germany.
Drug Metab Rev. 1994;26(1-2):325-48. doi: 10.3109/03602539409029801.
Metabolic activation of nitrogenous compounds by the cytochrome P-450 system is a highly complex process. Inherent substrate factors, such as basicity, electronic state, lipophilicity, and conformation control binding of the diverse classes of amines to cytochrome P-450. Accommodation of these compounds in the enzyme cavity and proper orientation of the molecules are governed by intrinsic properties of the peptide structure of cytochrome P-450, which may be subject to modification by the action of effectors. On the membrane level, phospholipid might have some impact on substrate binding. On the other hand, bound amine substrate is beneficial to the productive interaction of the electron transport chains with the terminal acceptor, improving economy of the system. Certain amines appear to regulate O2 association with cytochrome P-450 and stabilize the various oxy species formed. Considering the selective prerequisites for oxidative attack by cytochrome P-450 at vulnerable nitrogen centers, many cytotoxic amines belonging to the category of relatively rigid, planar molecules undergo N-oxidative activation by the cytochrome P-450IA subfamily, while more bulky amines with flexible conformation are N-oxygenated preferentially by phenobarbital-inducible cytochromes P-450. Small differences in protein structure between the various cytochrome P-450 subforms might serve to stabilize aminium radicals to permit oxygen rebound. Collectively, the selective regulatory mechanisms operative in the bioactivation of nitrogen-containing compounds appear to be determined largely by the type of substrate used and the isozyme involved in catalysis. With respect to the latter, the interplay of the multiple cytochromes P-450 in the various organs of animal species thus serves to rationalize the differences in the particular selectivities for amine substrates. These are responsible for the mode and/or extent to which activation of nitrogenous compounds, including promutagens and procarcinogens, occurs, and this may explain the tissue-specific response to the tumorigenic action of these agents.
细胞色素P-450系统对含氮化合物的代谢激活是一个高度复杂的过程。内在的底物因素，如碱性、电子状态、亲脂性以及不同种类胺类与细胞色素P-450的构象控制结合。这些化合物在酶腔中的容纳以及分子的正确取向受细胞色素P-450肽结构的内在特性支配，而这些特性可能会因效应器的作用而发生改变。在膜水平上，磷脂可能对底物结合有一定影响。另一方面，结合的胺底物有利于电子传递链与末端受体的有效相互作用，提高系统的经济性。某些胺似乎能调节氧气与细胞色素P-450的结合，并稳定形成的各种氧物种。考虑到细胞色素P-450在易损氮中心进行氧化攻击的选择性先决条件，许多属于相对刚性、平面分子类别的细胞毒性胺会被细胞色素P-450IA亚家族进行N-氧化激活，而构象较灵活的体积更大的胺则优先被苯巴比妥诱导的细胞色素P-450进行N-氧化。各种细胞色素P-450亚型之间蛋白质结构的微小差异可能有助于稳定铵自由基以允许氧反弹。总体而言，含氮化合物生物激活中起作用的选择性调节机制似乎在很大程度上取决于所用底物的类型和催化中涉及的同工酶。就后者而言，动物物种各器官中多种细胞色素P-450的相互作用因此有助于解释对胺底物特定选择性的差异。这些差异决定了含氮化合物（包括前诱变剂和前致癌物）激活的方式和/或程度，这可能解释了对这些物质致癌作用的组织特异性反应。
