Molecular mechanisms of the microsomal mixed function oxidases and biological and pathological implications.
Molecular mechanisms of the microsomal mixed function oxidases and biological and pathological implications.
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DOI：
10.1016/j.redox.2014.11.008
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发表时间：
2015
期刊：
影响因子：
11.4
通讯作者：
Cederbaum, Arthur I.
中科院分区：
文献类型：
--
作者：
Cederbaum, Arthur I.
关键词：
细胞色素P450混合功能氧化酶在重要内源底物的代谢和外源物质的生物转化中起着重要的作用。肝脏P450系统是外源底物代谢最活跃的系统。本文简要介绍了肝脏P450(CYP)混合功能氧化酶系统的酶组成和功能。NADPH-P450氧化还原酶的电子转移是还原P450的血红素所必需的，这是与分子氧结合所必需的。底物与P450的结合产生底物结合光谱。P450催化循环很复杂，限速步骤还不清楚。P450酶可以催化许多类型的化学反应，使该家族成为已知的最多样化的催化剂之一。根据结构同源性，有多种形式的P450排列成家族。从典型的底物、诱导剂和抑制剂以及它们的多晶型三个方面对主要药物代谢环磷酰胺进行了讨论。由于性别和年龄的差异、饮食的影响、肝病、潜在诱导物和/或抑制物的存在，人类的细胞色素P450的组成在个体之间有很大的差异。由于这些因素和CYP基因的多态性，以及重叠的药物特异性，P450酶的含量和组成在个体之间存在很大的差异。这可能会导致人类药物代谢的巨大变化，并往往会导致药物-药物相互作用和药物不良反应。由于上述诸多因素，尤其是细胞色素P450基因的多态性，个体化药物已引起人们的极大兴趣，尤其是关于存在哪些细胞色素P450及其多态形式，以试图确定什么药物治疗和什么剂量将反映治疗个体患者的最佳治疗策略。。细胞色素P450系统在内源性底物和药物代谢中起重要作用。大约有150种类型的细胞色素P4已被鉴定出来，并被归类为家族。环糊精催化各种各样的反应，是已知的最多样化的催化剂之一。电子通过NADPH+NADPH-细胞色素P450还原酶传递给细胞色素P450。某些化合物通过细胞色素P代谢会产生有毒的活性中间体。
The cytochrome P450 mixed function oxidase enzymes play a major role in the metabolism of important endogenous substrates as well as in the biotransformation of xenobiotics. The liver P450 system is the most active in metabolism of exogenous substrates. This review briefly describes the liver P450 (CYP) mixed function oxidase system with respect to its enzymatic components and functions. Electron transfer by the NADPH-P450 oxidoreductase is required for reduction of the heme of P450, necessary for binding of molecular oxygen. Binding of substrates to P450 produce substrate binding spectra. The P450 catalytic cycle is complex and rate-limiting steps are not clear. Many types of chemical reactions can be catalyzed by P450 enzymes, making this family among the most diverse catalysts known. There are multiple forms of P450s arranged into families based on structural homology. The major drug metabolizing CYPs are discussed with respect to typical substrates, inducers and inhibitors and their polymorphic forms. The composition of CYPs in humans varies considerably among individuals because of sex and age differences, the influence of diet, liver disease, presence of potential inducers and/or inhibitors. Because of such factors and CYP polymorphisms, and overlapping drug specificity, there is a large variability in the content and composition of P450 enzymes among individuals. This can result in large variations in drug metabolism by humans and often can contribute to drug–drug interactions and adverse drug reactions. Because of many of the above factors, especially CYP polymorphisms, there has been much interest in personalized medicine especially with respect to which CYPs and which of their polymorphic forms are present in order to attempt to determine what drug therapy and what dosage would reflect the best therapeutic strategy in treating individual patients. . The CYP P450 system is important in metabolism of endogenous substrates and drugs. About 150 forms of CYPs have been identified and they are grouped into families. CYPs catalyze a wide variety of reactions and are among the most diverse catalysts known. Electrons are passed to the CYP via NADPH+NADPH-cytochrome P450 reductase. Metabolism of certain compounds by CYPs generate reactive intermediates which are toxic.
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