Cavalieri E L, Rogan E G
Eppley Institute for Research in Cancer, University of Nebraska Medical Center, Omaha 68198-6805.
Free Radic Res Commun. 1990;11(1-3):77-87. doi: 10.3109/10715769009109670.
Most carcinogens, including polycyclic aromatic hydrocarbons (PAH), require metabolic activation to produce the ultimate electrophilic species that bind covalently with cellular macromolecules to trigger the cancer process. Metabolic activation of PAH can be understood in terms of two main pathways: one-electron oxidation to yield reactive intermediate radical cations and monooxygenation to produce bay-region diol epoxides. The reason we have postulated that one-electron oxidation plays an important role in the activation of PAH derives from certain common characteristics of the radical cation chemistry of the most potent carcinogenic PAH. Two main features common to these PAH are: 1) a relatively low ionization potential, which allows easy metabolic removal of one electron, and 2) charge localization in the PAH radical cation that renders this intermediate specifically and efficiently reactive toward nucleophiles. Equally important, cytochrome P-450 and mammalian peroxidases catalyze one-electron oxidation. This mechanism plays a role in the binding of PAH to DNA. Chemical, biochemical and biological evidence will be presented supporting the important role of one-electron oxidation in the activation of PAH leading to initiation of cancer.
大多数致癌物，包括多环芳烃（PAH），都需要代谢激活才能产生最终的亲电物质，这些亲电物质与细胞大分子共价结合，从而引发癌症进程。PAH的代谢激活可以通过两条主要途径来理解：单电子氧化生成反应性中间体自由基阳离子，以及单加氧反应生成湾区二醇环氧化物。我们推测单电子氧化在PAH激活过程中起重要作用的原因，源于最具致癌性的PAH自由基阳离子化学的某些共同特征。这些PAH共有的两个主要特征是：1）相对较低的电离电位，这使得代谢过程中易于去除一个电子；2）PAH自由基阳离子中的电荷定位，使得该中间体对亲核试剂具有特异性和高效反应性。同样重要的是，细胞色素P-450和哺乳动物过氧化物酶催化单电子氧化。这种机制在PAH与DNA的结合中起作用。将提供化学、生物化学和生物学证据，支持单电子氧化在PAH激活导致癌症起始过程中的重要作用。
