细胞色素P450酶系在药物代谢中的作用

该文从细胞色素P450概述、参与药物代谢的人类细胞色素P450亚型、细胞色素P450与药物的相互作用、细胞色素P450多态性在药物不良反应中的作用及细胞色素P450酶系产生药物不良反应的机制等方面综述细胞色素P450酶系对药物代谢的影响，为指导临床合理用药，避免药物不良反应及个体化用药提供参考。     

细胞色素P450酶与药物选用

目的了解细胞色素P450酶与药物代谢关系,加强认识有利于临床药物选用。方法通过收集文献了解细胞色素P450酶在药物代谢中的作用。结果与结论正确认识细胞色素P450酶的特点,有利于临床药物选用,提高合理用药的水平。     

炎症过程中细胞色素P450酶活性降低及其机制的研究进展

机体在感染或炎症状态下,肝脏细胞色素P450药物代谢酶mRNA表达和蛋白含量显著降低,酶的催化活性降低。这种变化对人体内药物代谢过程乃至相关药物临床治疗安全性具有显著影响。细胞色素P450异构酶活性降低具有不同的变化过程与模式,反映细胞色素P450酶系具有多种活性调节机制。现有研究表明,细胞色素P450酶活性降低主要发生在基因表达环节,由多种炎症细胞因子介导。阐明炎症对细胞色素P450活性的影响有助于明确细胞色素P450酶活性的调控机制,对指导临床安全合理用药具有重要意义。     

细胞色素P450临床不合理用药分析

目的 阐述细胞色素P450在临床联合用药中的重要性,对临床不合理联合用药进行干预.方法 对临床药师在查房中搜集到的典型的不合理用药案例中与细胞色素P450有关的病例进行用药分析.结果 临床药师能及时发现、解决潜在的与细胞色素P450相关的不合理用药现象.结论 通过临床药师的干预,确保临床用药的安全、有效、合理,促进药物合理使用,减少不良反应的发生.     

细胞色素P450基因多态性对药物疗效和安全性的影响

目的：根据细胞色素CYP450基因多态性的分子调控、种族差异及基因多态性对药物疗效和安全性的影响等进行综述。方法：对相关细胞色素P450氧化酶的文献报道进行综合分析与评论。结果：细胞色素P450氧化酶是药物代谢的主要酶系统。人肝脏有20多个CYP450亚家族．细胞色素P450氧化酶的基因具有遗传多态性,该遗传多态性具有明显种族差异。结论：细胞色素P450氧化酶影响药物代谢动力学、药效学和临床使用安全性。     

细胞色素P450酶系介导的甾体羟化反应及其在分子水平上的研究进展

细胞色素P450单加氧酶系(cytochrome P450 monooxygenases,P450s)是主要位于某些细胞的内质网上的一个氧化酶系.P450酶系介导羟化反应是微生物甾体化合物转化反应中最重要的反应.本文概述了微生物细胞色素P450酶系,并注重综述了细胞色素P450酶系基因在转录水平调控、克隆表达以及在甾体转化应用、药物代谢等分子水平方面的研究进展.     

与细胞色素P450亚型酶代谢相关的药物

细胞色素P450（CYP450）是人体内广泛存在的、具有复杂功能的酶系统,是药物代谢的主要途径。本文主要介绍用于细胞色素P450亚型酶的代谢底物及其诱导剂、抑制剂等,为研究药物在体内的代谢提供基础,指导临床合理用药。     

细胞色素P450酶对肿瘤易感性及药物代谢的研究进展

CYP450是人体中参与药物代谢的重要酶系之一,催化多种内源、外源化合物,特别是多种临床药物的生物转化。近年来,对细胞色素P450的结构、功能、药物代谢及其基因型和表型相关性的研究越来越受到重视。本文通过查阅国内外相关文献综述了近年来关于CYP450基因多态性与肿瘤易感性和药物代谢方面的研究进展。     

CYP450氧化还原酶遗传多态性对CYP酶影响的研究进展

细胞色素P450氧化还原酶(Cytochrome P450 0xidoreductase,POR)是将电子从NADPH转运至所有肝微粒体的细胞色素P450氧化酶(Cytochrome P450 monooxygenases,CYP)中的唯一供体.药物、类固醇激素等物质的代谢和转化需要CYP参与.POR基因具有遗传多态性,遗传变异可以改变CYP活性,引起P450氧化还原酶缺陷(P450 0xidoreductase deficiency,PORD)、临床药物代谢和反应差异.本文将从POR的结构功能、基因突变引起的疾病及其对酶活性影响三个方面进行论述,总结近年来POR遗传多态性对CYP酶影响的最新研究进展.     

新型抗抑郁剂与细胞色素P450系统

细胞色素P450同功酶大部分局限在肝细胞内质网上，与其同系的有30多个相关酶，涉及不同种类药物及内源性物质如前列腺素、脂肪酸和类固醇的氧化代谢。许多抗抑郁剂和抗精神病药均受一种或多种细胞色素P450同功酶的代谢或不同程度的抑制。清楚地了解细胞色素P450同功酶的底物和抑制剂，有助于预见临床上所发生的明显药物相互作用。但首先要认识构成药物代谢个体差异基础的某些细胞色素P450同功酶在功能表达上的遗传多形性。近年来所开发的许多新型抗抑郁剂包括选择性血清素再摄取抑制剂（SSRI），也是细胞色素P450同系酶中不同种类同功酶…     

细胞色素P450 2D6、3A4和19A1基因多态性与乳腺癌的药物治疗

细胞色素P450(CYP)是一种重要的氧化代谢酶,参与多种药物的代谢。CYP酶具有基因多态性,对药物的代谢呈现明显的差异,对乳腺癌用药也有差异性影响。该文主要阐述细胞色素P450 2D6、3A4和19A1亚型的多态性,并就其多态性对临床乳腺癌治疗中重要的药物如他莫昔芬、芳香化酶抑制剂、紫杉醇类在治疗学方面的影响进行综述。     

植物药及果蔬对药物代谢酶P450活性的影响

中草药及其他植物药在我国及东南亚国家应用广泛，在欧美也逐渐受到重视，一些中草药及植物药可能诱导或抑制肝脏细胞色素P450(CYP)药物代谢酶，从而引起自身及其他合用药物代谢的改变，因此可能导致药物不良反应和药物相互作用。     

HUMAN CYTOCHROME P450 ENZYMES EXPRESSED IN BACTERIA: REAGENTS TO PROBE MOLECULAR INTERACTIONS IN TOXICOLOGY

1. Phase I metabolism of drugs is accomplished by the concerted actions of a limited number of cytochrome P450 enzymes with wide but often overlapping substrate specificities. Although metabolism generally accelerates the clearance of drugs, reactive products may also be generated that cause toxic effects. 2. Because individuals vary in the range and levels of different P450 forms, it is useful to be able to determine the specific isoforms involved in a particular metabolic reaction, in order to estimate the extent of variation within a population in the pharmacokinetics of specific drugs. Such studies may also allow predictions to be made regarding the relative susceptibility of different individuals to possible adverse effects associated with drug treatment. 3. Human cytochrome P450 enzymes are now routinely expressed as recombinant proteins in many different systems, including mammalian cell culture, yeast, baculovirus and Escherichia coli. The latter system is particularly useful when large amounts of protein are required for biophysical studies, but can also be adapted to routine examination of pathways of drug metabolism and toxicology. 4. The present review provides an analysis of strategies used for enhancing cytochrome P450 expression in bacteria and for examining the activity of the recombinant proteins. The potential applications of recombinant P450 are discussed, with particular emphasis on investigation of the roles of cytochrome P450 forms in the metabolism and the toxicity of drugs.     

细胞色素P450活性与癌症治疗

本文通过总结影响细胞色素P450活性的因素和抗肿瘤药的生物转化途径,以期探索细胞色素P450同工酶介导的代谢在抗癌药物体内生物转化中的作用,进而探索该酶活性与癌症患者的疗效之间的相关性。发现化疗药物的个体间药代动力学差异会引起治疗的疗效和安全性的不同结果。年龄、性别、单个基因多态性等单一因素并不能阐明个体间对药物反应的差异性,化疗方案中多个药物的相互作用在临床上非常重要。为了更好地评估细胞色素P450酶类对机体代谢的作用,药物的吸收、排泄、活化,以及代谢整个药代动力学途径涉及的酶的多态性都应进行研究。     

Proteome studies on liver tissue in a phenobarbital-induced rat model

Many drugs may affect the activity of cytochrome P450 (CYP), which is a major source of adverse drug interactions (ADR). Phenobarbital (PB) is the typical inducer of cytochrome P450. The aim of our study was to determine the changes in the cytosolic proteins expression in rat liver at a protein level following induction of cytochrome P450. Firstly, we made a phenobarbital-induced cytochrome P450 rat model. The total cytosolic proteins were then extracted from rat liver tissue and separated by 2-D gel electrophoresis (2-DE). Differentially expressed spots were identified by MALDI-TOF/TOF tandem mass spectrometry followed by database searching. Eight differentially expressed proteins were identified and these proteins were found to be involved in protein degradation, oxidative stress, energy metabolism, biotransformation, and the synthesis of quinolinic acid (QUIN). These findings should provide useful information for research into the regulation of cytochrome P450 gene expression, drug metabolism and drug interaction.     

Monoclonal antibodies and multifunctional cytochrome P450: drug metabolism as paradigm

Monoclonal antibodies are reagents par excellence for analyzing the role of individual cytochrome P450 isoforms in multifunctional biological activities catalyzed by cytochrome P450 enzymes. The precision and utility of the monoclonal antibodies have heretofore been applied primarily to studies of human drug metabolism. The unique and precise specificity and high inhibitory activity toward individual cytochrome P450s make the monoclonal antibodies extraordinary tools for identifying and quantifying the role of each P450 isoform in the metabolism of a drug or nondrug xenobiotic. The monoclonal antibodies identify drugs metabolized by individual, several, or polymorphic P450s. A comprehensive collection of monoclonal antibodies has been isolated to human P450s: 1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C family, 2C19, 2D6, 2E1, 3A4/5, and 2J2. The monoclonal antibodies can also be used for identifying drugs and/or metabolites useful as markers for in vivo phenotyping. Clinical identification of a patient's phenotype, coupled with precise knowledge of a drug's metabolism, should lead to a reduction of adverse drug reactions and improved drug therapeutics, thereby promoting advances in drug discovery.     

The hepatic cytochrome P450 reductase null mouse as a tool to identify a successful candidate entity

Cytochrome P450s (CYP) play a pivotal role in the metabolism of drugs and xenobiotics, and have been intensively studied over many years. Much of the work carried out on the role of hepatic cytochrome P450s in drug metabolism and disposition has been done in vitro, and has yielded vital information on P450 regulation and function. However, additional factors such as route of administration, absorption, drug transporters, renal clearance and extra-hepatic P450s, make it difficult to extrapolate from in vitro data to in vivo pharmacokinetics. A number of cytochrome P450s knockout mice have been generated, although many have been of limited usefulness due to either embryonic/perinatal lethality, or the functional redundancy inevitably found in a large family of isoenzymes. We have developed a mouse line (HRN) in which cytochrome P450 oxidoreductase (POR), the unique electron donor to cytochrome P450s is deleted specifically in the liver, resulting in the loss of essentially all hepatic P450 function. The HRN mouse, although having disturbances in lipid and bile acid homeostasis develops and breeds normally. We have used the HRN mouse as a model to establish the role of hepatic versus extra-hepatic metabolism in drug metabolism and disposition, and also to investigate the relationship between drug toxicokinetics and therapeutic effect, initially with the chemotherapeutic prodrug cyclophosphamide (CPA).     

Application of support vector machines to in silico prediction of cytochrome p450 enzyme substrates and inhibitors

Cytochrome P450 enzymes are responsible for phase I metabolism of the majority of drugs and xenobiotics. Identification of the substrates and inhibitors of these enzymes is important for the analysis of drug metabolism, prediction of drug-drug interactions and drug toxicity, and the design of drugs that modulate cytochrome P450 mediated metabolism. The substrates and inhibitors of these enzymes are structurally diverse. It is thus desirable to explore methods capable of predicting compounds of diverse structures without over-fitting. Support vector machine is an attractive method with these qualities, which has been employed for predicting the substrates and inhibitors of several cytochrome P450 isoenzymes as well as compounds of various other pharmacodynamic, pharmacokinetic, and toxicological properties. This article introduces the methodology, evaluates the performance, and discusses the underlying difficulties and future prospects of the application of support vector machines to in silico prediction of cytochrome P450 substrates and inhibitors.     

Recent progress on bioinformatics, functional genomics, and metabolomics research of cytochrome P450 and its impact on drug discovery

The cytochrome P450 superfamily is responsible primarily for human drug metabolism, which is of critical importance for the drug discovery and development. Rapid advancement of bioinformatics, functional genomics and metabolomics has been made over the last decade. These disciplines are essential in target identification, lead discovery and optimization. In this review, we summarize the recent progress on cytochrome P450 and its role on drug metabolism in the context of bioinformatics, functional genomics and metabolomics. Data are integrated into various databases and web-based platforms on cytochrome P450. These research tools and resources are playing an increasingly important role in drug discovery, and are helping in achieving the ultimate goal of personalized medicine, that is, to prescribe personalized drugs according to each person's genetic makeup, metabolic level, and drug disposition.     

Cytochrome P450s and other enzymes in drug metabolism and toxicity

The cytochrome P450 (P450) enzymes are the major catalysts involved in the metabolism of drugs. Bioavailability and toxicity are 2 of the most common barriers in drug development today, and P450 and the conjugation enzymes can influence these effects. The toxicity of drugs can be considered in 5 contexts: on-target toxicity, hypersensitivity and immunological reactions, off-target pharmacology, bioactivation to reactive intermediates, and idiosyncratic drug reactions. The chemistry of bioactivation is reasonably well understood, but the mechanisms underlying biological responses are not. In the article we consider what fraction of drug toxicity actually involves metabolism, and we examine how species and human interindividual variations affect pharmacokinetics and toxicity.