Davydov D R
Institute of Biomedical Chemistry, Moscow, Russia; Department of Chemistry, Washington State University, Washington, USA.
Biomed Khim. 2015 Mar-Apr;61(2):176-87. doi: 10.18097/PBMC20156102176.
The central role that cytochromes P450 play in the metabolism of drugs and other xenobiotics makes these enzymes a major subject for studies of drug disposition, adverse drug effects and drug-drug interactions. Although there has been tremendous success in delineating P450 mechanisms, the concept of the drug-metabolizing ensemble as a functionally integrated system remains undeveloped. However, eukaryotic cells typically possess a multitude of different P450 enzymes that are co-localized in the membrane of endoplasmic reticulum (ER) and interact with each other with the formation of dynamic heteromeric complexes (mixed oligomers). Appreciation of the importance of developing an integral, systems approach to the ensemble of cytochromes P450 as an integral system inspired growing interest of researchers to the molecular organization of microsomal monooxygenase, which remained in the focus of research of academician Archakov for over 40 years. Fundamental studies carried out under his guidance have an important impact on our current concepts in this area. Further exploration of the molecular organization of the system of microsomal monooxygenase as an integral multienzyme and multifunctional system will have an essential impact on our understanding of the key factors that determine the changes in human drug metabolism and other P450-related functions in development, aging, and disease, as well as under influence of drugs, food ingredients, and environmental contaminants.
细胞色素P450在药物及其他异源生物代谢中发挥的核心作用，使这些酶成为药物处置、药物不良反应和药物相互作用研究的主要对象。尽管在阐明P450机制方面已取得了巨大成功，但将药物代谢酶系视为一个功能整合系统的概念仍未得到充分发展。然而，真核细胞通常拥有多种不同的P450酶，它们共定位于内质网（ER）膜中，并相互作用形成动态异源复合物（混合寡聚体）。认识到开发一种整体的、系统的方法来研究细胞色素P450酶系作为一个整体系统的重要性，激发了研究人员对微粒体单加氧酶分子组织的日益浓厚兴趣，在40多年的时间里，这一直是阿尔恰科夫院士研究的重点。在他的指导下进行的基础研究对我们目前在这一领域的概念产生了重要影响。进一步探索微粒体单加氧酶系统作为一个完整的多酶和多功能系统的分子组织，将对我们理解决定人类药物代谢及其他与P450相关功能在发育、衰老和疾病过程中以及在药物、食品成分和环境污染物影响下发生变化的关键因素产生至关重要的影响。
