细胞色素P450酶与药物相互作用研究进展

美国的一项研究表明,住院患者的严重不良反应发生率为6.7%,因药物相互作用的致死率已排名住院患者死亡原因的第4~5位[1]。近20 a内,美国FDA先后已将批准上市的13种新药从市场撤出,其最主要的原因就是出现了严重的药物代谢性相互作用[2]。近来研究人员在新药的早期研发阶段,应用     

基于细胞色素P450酶诱导的药物相互作用及评价

药物研发阶段候选物的淘汰率很高,原因之一是候选物对代谢酶的诱导或抑制活性有可能导致临床的代谢性药物相互作用。因此,新药候选物对已上市药物及其自身代谢动力学的改变是影响药物治疗的一个关键代谢性质,新药候选物酶诱导能力的评价已成为新药研发过程中的重要环节。细胞色素P450（CYP）是介导大部分外源性和内源性物质的代谢酶,CYP酶诱导引起的代谢性药物相互作用能导致合用药物的代谢消除加快,影响药物临床应用的有效性和安全性。本文就CYP酶诱导的药物相互作用对药物临床应用的影响以及新药候选物酶诱导能力评价方法的研究进展进行综述。     

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。     

中成药对细胞色素P450酶的影响

通过参阅大量近年来国内外有关中成药对药物代谢酶细胞色素P450酶影响的文献,对中成药对细胞色素P450酶的研究的文献进行整理和分析.发现一些中成药对细胞色素P450酶确实存在不同程度的抑制或诱导作用.因此深入研究中成药对细胞色素P450酶活性的影响,既有助于指导中成药在临床上的合理使用以避免因药物相互作用导致的不良反应...     

细胞色素P450酶系和药物的不良反应

细胞色素P450酶系在药物代谢中扮演了重要角色.本文描述了许多环境的和基因的因素,这些因素调整人体酶和它们的药物底物的活性.在一些情况下,细胞色素P450酶具有基因的多态性,导致对某些药物在表型上明显慢和明显快的代谢.慢代谢者(PMs)易发生与浓度相关的药物不良反应,而快代谢者(EMs)则对药物相互作用易感;其中抑制的相互作用可能会由于血浆浓度的增加而导致毒性.药物代谢被改变是药物不良反应的重要原因.     

细胞色素P450系统与蛋白酶抑制剂的药物相互作用

简述了细胞色素P450（CYP）系统的同工酶命名、异构体类型和基因多态性表达，并介绍了酶抑制剂和酶诱导剂的动力学特性。阐述了蛋白酶抑制剂沙奎那韦、茚地那韦、利托那韦与其他经CYP代谢的药物合用时出现的药物相互作用。     

细胞色素P450酶和P-gp介导药物相互作用的体外研究方法

药物相互作用一般分为药动学相互作用和药效学相互作用2大类。药动学相互作用可发生在吸收、分布、代谢、排泄4个阶段,其中由细胞色素P450酶系介导的代谢性相互作用发生率最高。同细胞色素P450酶一样,P-糖蛋白(P-glycoprotein,P-gp)由于在其底物的吸收、分布和排泄等药动学过程中发挥着重要作用,同样可介导体内多种药物间的相互作用[1]。随着对药物相互作用分子水平的认识和体外研究技术的进步,临床前的体外试验基本上可以预测药物在体内发生相互作用的过程,从而大大减少上市后因严重相互作用而被淘汰的巨大风险,对未来开发新药具有重要意…     

细胞色素P450酶系和药物不良反应

细胞色素P450酶系在药物代谢中扮演了重要角色。本描述了许多环境和基因的因素,这些因素调整人体酶和它们的药物底物的活性。在一些情况下,细胞色素P450酶具有基因的多态性,导致对某些药物在表型上明显慢和明显快的代谢。慢代谢（PMs）易发生与浓度相关的药物不良反应,而快代谢（EMs）则对药物相互作用易感;其中抑制的相互作用可能会由于血浆浓度的增中而导致毒性。药物代谢被改变是药物不良反应的重要原因。     

食物,细胞色素P450酶与药物代谢

细胞色素Ｐ４５０系列酶对药物及外源性化合物的人体内代谢具有影响，有的可使之提高药效，减少毒副反应，有的可降低药效，增加毒性，甚至致癌。而食物可改变体内各种Ｐ４５０异检酶的含量和活性，因而可对药物代谢发挥间接作用。     

基于细胞色素P450的左金丸体外药物相互作用研究

目的:探讨左金丸对人肝细胞色素P450的CYP1A2/2C8/2C9/2C19/2D6/3A4亚型的体外抑制作用。方法:左金丸、黄连和吴茱萸的水提物分别与CYP1A2/2C8/2C9/2C19/2D6/3A4/3A4亚型的7种混合探针底物在人肝微粒体中共同孵育后,采用液相色谱-串联质谱法（LC-MS/MS）同时测定这7种代谢产物（对乙酰氨基酚/6α-羟基紫杉醇/4-羟基双氯芬酸/4-羟基美芬妥英/右啡烷/1-羟基咪达唑仑/6β-羟基睾酮）的浓度,计算其IC₅₀值表示对该亚型的抑制程度。结果:在人肝微粒体体外孵育体系中,左金丸提取物对CYP2D6的IC₅₀值为11.6μg·ml^-1,对CYP1A2和CYP3A4的IC₅₀值分别为77.4μg·ml^-1和97.0μg·ml^-1,对其他亚型的IC₅₀值从334μg·ml^-1到690μg·ml^-1;黄连提取物对CYP2D6的IC₅₀值为5.8μg·ml^-1,对CYP1A2和CYP3A4的IC₅₀值分别为36.8μg·ml^-1和59.2μg·ml^-1,对其他亚型的IC₅₀值从163μg·ml^-1到476μg·ml^-1;吴茱萸提取物对CYPs的IC₅₀值均大于107μg·ml^-1。结论:左金丸在体外对人肝微粒体CYP2D6活性有抑制作用,对CYP1A2和CYP3A4活性有弱的抑制作用,其君药黄连在该抑制作用中起到了主要作用,在联合用药时应注意左金丸与CYP2D6相关的药物相互作用。     

细胞色素P450酶与药物代谢的研究进展与评价

目的：评价细胞色素P450酶与药物代谢的研究进展,以供临床医师合理用药参考。方法：查阅近年来国内、外的相关文献资料,进行归纳和分析。结果与结论：肝细胞色素P450酶系参与人体许多内、外源性物质（包括药物）的分解和代谢。P450酶系在体内的分布、结构和功能在药物代谢和临床疾病诊断过程中有着十分重要的药理作用和临床意义。     

细胞因子与细胞色素P450

随着生物技术的发展,细胞因子的生物工程产品已越来越多地应用于临床治疗。本文通过对近年国外文献分析总结,综述了细胞因子对细胞色素P450的活性及其使RNA的表达影响,从中可以了解细胞因子对细胞色素P450的调节作用,对细胞因子在临床上的合理应用的重要意义。     

葛根素对5种细胞色素P450酶体外活性影响研究

目的 研究葛根素体外对细胞色素P450酶亚型 CYP1A2、CYP2C9、CYP2C19、CYP2D6和CYP3A4等活性的影响。方法分别以咖啡因、甲苯磺丁脲、美芬妥因、美托洛尔和咪哒唑仑为探针药，采用高效液相色谱法测定探针药与相应代谢产物的浓度，采用重组酶研究葛根素对CYP1A2、CYP2C9、CYP2C19、CYP2D6和CYP3A4酶体外活性的影响。结果在体外重组酶反应体系中，葛根素对CYP2C9、CYP2C19及CYP3A4酶活性无明显影响。但低浓度(0.1 mmol·L 1)下可使CYP1A2活性降低 (48±9)%(P＜0.05)，使CYP2D6活性降低(61±8)%(P＜0.01)；高浓度(0.4 mmol·L 1)下使CYP1A2活性降低（82 ±8）%(P＜0.01)，使CYP2D6活性降低（88 ± 6）%(P＜ 0.01)。结论葛根素对CYP1A2和CYP2D6酶体外活性有较明显的抑制作用；随着葛根素浓度的增高，抑制作用也相应增强。     

细胞色素P450和医学

细胞色素P450(CYP,P450)是一个血红蛋白家族的通用名称.这是一个非常巨大、种类丰富的酶家族,广泛存在于进化谱系所有生物体中(从细菌到人).已经发现和命名的不同CYP蛋白超过11500个(截止至2009年2月),但只有少数进行了详细研究.该家族参与到生命进程中众多的新陈代谢反应,包括羟基化、N-,O-,和S-脱烷基化、磺化氧化、环氧化、脱氨、脱硫、脱卤、过氧化和N-氧化还原作用.本文介绍了细胞色素P450的研究历史、结构、命名法、分类及功能.人类和动物细胞色素P450酶类与诸多疾病相关,尤其是肝病和癌症.三个细胞色素P450基因家族(CYP 1,CYP2和CYP3)似乎参与大量抗生素代谢反应.人们正在深入研究CYP450的功能,为不久的将来能战胜肝病、癌症和其他疾病提供可能性.     

Inhibition of Cytochrome P450 Enzymes by Drugs—Molecular Basis and Practical Applications

Drug-drug interactions are a major cause of hospitalization and deaths related to drug use. A large fraction of these is due to inhibition of enzymes involved in drug metabolism and transport, particularly cytochrome P450 (P450) enzymes. Understanding basic mechanisms of enzyme inhibition is important, particularly in terms of reversibility and the use of the appropriate parameters. In addition to drug-drug interactions, issues have involved interactions of drugs with foods and natural products related to P450 enzymes. Predicting drug-drug interactions is a major effort in drug development in the pharmaceutical industry and regulatory agencies. With appropriate in vitro experiments, it is possible to stratify clinical drug-drug interaction studies. A better understanding of drug interactions and training of physicians and pharmacists has developed. Finally, some P450s have been the targets of drugs in some cancers and other disease states.     

细胞色素P450酶与维生素A的代谢

维生素A是人体必不可少的一种脂溶性维生素,在体内可以代谢为生物活性更高的视黄醛和视黄酸。细胞色素P450酶是重要的药物Ⅰ相代谢酶,在人体内有广泛的分布。它不仅参与了外源性物质的代谢,在内源性物质的代谢中也有重要的作用。CYP450酶在维生素A的代谢中扮演了重要的角色。人体内参与维生素A代谢的CYP450酶主要是CYP1,CYP2C,CYP2E,CYP3A和CYP26家族。同时其代谢物视黄酸可以与核受体(维生素A酸受体,视黄醇类X受体)相结合,诱导CYP450酶的表达和活性。本文通过对近几年来维生素A代谢的研究进展做一综述,阐述了CYP1、CYP2C、CYP2E、CYP3A和CYP26家族在维生素A代谢中的作用以及视黄酸诱导CYP450酶的分子机制。     

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.     

Cytochrome P450 reductase dependent inhibition of cytochrome P450 2B1 activity: Implications for gene directed enzyme prodrug therapy

Cytochrome P450 (P450) enzymes are often used in suicide gene cancer therapy strategies to convert an inactive prodrug into its therapeutic active metabolites. However, P450 activity is dependent on electrons supplied by cytochrome P450 reductase (CPR). Since endogenous CPR activity may not be sufficient for optimal P450 activity, the overexpression of additional CPR has been considered to be a valuable approach in gene directed enzyme prodrug therapy (GDEPT). We have analysed a set of cell lines for the effects of CPR on cytochrome P450 isoform 2B1 (CYP2B1) activity. CPR transfected human embryonic kidney 293 (HEK293) cells showed both strong CPR expression in Western blot analysis and 30-fold higher activity in cytochrome c assays as compared to parental HEK293 cells. In contrast, resorufin and 4-hydroxy-ifosfamide assays revealed that CYP2B1 activity was up to 10-fold reduced in CPR/CYP2B1 cotransfected HEK293 cells as compared to cells transfected with the CYP2B1 expression plasmid alone. Determination of ifosfamide-mediated effects on cell viability allowed independent confirmation of the reduction in CYP2B1 activity upon CPR coexpression. Inhibition of CYP2B1 activity by CPR was also observed in CYP2B1/CPR transfected or infected pancreatic tumour cell lines Panc-1 and Pan02, the human breast tumour cell line T47D and the murine embryo fibroblast cell line NIH3T3. A CPR mediated increase in CYP2B1 activity was only observed in the human breast tumour cell line Hs578T. Thus, our data reveal an effect of CPR on CYP2B1 activity dependent on the cell type used and therefore demand a careful evaluation of the therapeutic benefit of combining cytochrome P450 and CPR in respective in vivo models in each individual target tissue to be treated.     

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。     

Analysis of the Interactions of Cytochrome b5 with Flavocytochrome P450 BM3 and its Domains

Interactions between a soluble form of microsomal cytochrome b₅ (b₅) from Musca domestica (housefly) and Bacillus megaterium flavocytochrome P450 BM3 and its component reductase (CPR), heme (P450) and FAD/NADPH-binding (FAD) domains were analyzed by a combination of steady-state and stopped-flow kinetics methods, and optical spectroscopy techniques. The high affinity binding of b₅ to P450 BM3 induced a low-spin to high-spin transition in the P450 heme iron (K_d for b₅ binding?=?0.44 μM and 0.72 μM for the heme domain and intact flavocytochrome, respectively). The b₅ had modest inhibitory effects on steady-state turnover of P450 BM3 with fatty acids, and the ferrous-carbon monoxy P450 complex was substantially stabilized on binding b₅. Single turnover reduction of b₅ by BM3 using stopped-flow absorption spectroscopy (k_lim?=?116 s^?1) was substantially faster than steady-state reduction of b₅ by P450 BM3 (or its CPR and FAD domains), indicating rate-limiting step(s) other than BM3 flavin-to-b₅ heme electron transfer in the steady-state reaction. Steady-state b₅ reduction by P450 BM3 was considerably accelerated at high ionic strength. Pre-reduction of P450 BM3 by NADPH decreased the k_lim for b₅ reduction ～10-fold, and also resulted in a lag phase in steady-state b₅ reduction that was likely due to BM3 conformational perturbations sensitive to the reduction state of the flavocytochrome. Ferrous b₅ could not reduce the ferric P450 BM3 heme domain under anaerobic conditions, consistent with heme iron reduction potentials of the two proteins. However, rapid oxidation of both hemoproteins occurred on aeration of the ferrous protein mixture (and despite the much slower autoxidation rate of b₅ in isolation), consistent with electron transfer occurring from b₅ to the oxyferrous P450 BM3 in the complex. The results demonstrate that strong interactions occur between a eukaryotic b₅ and a model prokaryotic P450. Binding of b₅ perturbs BM3 heme iron spin-state equilibrium, as is seen in many physiologically relevant b₅ interactions with eukaryotic P450s. These results are consistent with the conservation of structure of P450s (particularly at the heme proximal face) between prokaryotes and eukaryotes, and may point to as yet undiscovered roles for b₅-like proteins in the control of activities of certain prokaryotic P450s.