Analytical Biochemistry and Mass Spectrometry Core Facility, Department of Pharmacy, University of Groningen, A. Deusinglaan 1, 9713 AV Groningen, The Netherlands.
Curr Drug Metab. 2011 May;12(4):359-71. doi: 10.2174/138920011795202929.
Prediction of oxidative drug metabolism at the early stages of drug discovery and development requires fast and accurate analytical techniques to mimic the in vivo oxidation reactions by cytochrome P450s (CYP). Direct electrochemical oxidation combined with mass spectrometry, although limited to the oxidation reactions initiated by charge transfer, has shown promise in the mimicry of certain CYP-mediated metabolic reactions. The electrochemical approach may further be utilized in an automated manner in microfluidics devices facilitating fast screening of oxidative drug metabolism. A wide range of in vivo oxidation reactions, particularly those initiated by hydrogen atom transfer, can be imitated through the electrochemically-assisted Fenton reaction. This reaction is based on O-O bond activation in hydrogen peroxide and oxidation by hydroxyl radicals, wherein electrochemistry is used for the reduction of molecular oxygen to hydrogen peroxide, as well as the reduction of Fe(3+) to Fe(2+). Metalloporphyrins, as surrogates for the prosthetic group in CYP, utilizing metallo-oxo reactive species, can also be used in combination with electrochemistry. Electrochemical reduction of metalloporphyrins in solution or immobilized on the electrode surface activates molecular oxygen in a manner analogous to the catalytical cycle of CYP and different metalloporphyrins can mimic selective oxidation reactions. Chemoselective, stereoselective, and regioselective oxidation reactions may be mimicked using electrodes that have been modified with immobilized enzymes, especially CYP itself. This review summarizes the recent attempts in utilizing electrochemistry as a versatile analytical and preparative technique in the mimicry of oxidative drug metabolism by CYP.
在药物发现和开发的早期阶段，预测氧化药物代谢需要快速而准确的分析技术来模拟细胞色素 P450（CYP）的体内氧化反应。直接电化学氧化结合质谱，虽然仅限于通过电荷转移引发的氧化反应，但在模拟某些 CYP 介导的代谢反应方面显示出了前景。电化学方法可以进一步在微流控设备中以自动化的方式使用，从而促进氧化药物代谢的快速筛选。广泛的体内氧化反应，特别是那些由氢原子转移引发的反应，可以通过电化学辅助的芬顿反应来模拟。该反应基于过氧化氢中的 O-O 键活化和羟基自由基的氧化，其中电化学用于将分子氧还原为过氧化氢，以及将 Fe(3+)还原为 Fe(2+)。金属卟啉作为 CYP 中辅基的替代物，利用金属-氧反应性物质，也可以与电化学结合使用。金属卟啉在溶液中的电化学还原或在电极表面的固定化以类似于 CYP 催化循环的方式激活分子氧，并且不同的金属卟啉可以模拟选择性氧化反应。可以使用固定化酶（特别是 CYP 本身）修饰的电极模拟化学选择性、立体选择性和区域选择性氧化反应。本综述总结了最近利用电化学作为一种通用的分析和制备技术在模拟 CYP 氧化药物代谢方面的尝试。
