从细胞色素P_(450)角度分析2005年版《中国药典》收载的中成药与其他药物配伍使用的合理性

由细胞色素P450酶系催化的Ⅰ相反应是药物体内代谢转化的关键性步骤,它可以影响药物的半衰期、清除率和生物利用度等多种重要的药动学特性。P450酶系具有的可诱导和可抑制的特性,使许多化学物质对P450酶可产生诱导或抑制作用,进而使某些P450酶的量和活性增加或降低,可见,一些外源性物质可影响P450酶对其底物的代谢[1]。大量的研究报道表明,某些中药对P450酶系的作用可影响其他药物的代谢[2,3]。为提高临床合理用药水平,给临床用药提供参考,笔者特对2005年版《中国药典》中收载的含有对人肝细胞微粒体P450酶系有影响的中成药进行归纳报道…     

细胞色素P450的基因多态性与药物代谢

细胞色素P450（cytochrome P450，CYP）是重要的药物代谢酶，参与催化多种内源和外源化合物，特别是多种临床药物的生物转化。CYP存在广泛的基因多态性和表型多态性，使其对于各种化合物的代谢存在统计学个体差异。核受体是配体依赖性转录因子超家族，与药物代谢过程中的基因表达调控密切相关，被外源物质活化后诱导或抑制CYP基因的表达。现综述CYP与药物代谢、CYP的基因多态性、CYP表达的诱导机制、核受体及其配体诱导CYP表达及近年研究CYP450的各种实验方法。     

植物成分与细胞色素P450相互作用的研究进展

细胞色素P450（CYP450）是体内参与药物代谢的重要酶系,其活性在受到诱导或抑制后将干扰药物的作用。植物成分普遍存在于食物与药物中,与CYP450的相互作用将产生广泛影响。总结近年来植物成分与细胞色素P450的7个亚型CYP1A2、CYP2A6、CYP2C9、CYP2C19、CYP2D6、CYP2E1、CYP3A4相互作用的研究结果,为临床上合理用药提供参考。     

植物成分与细胞色素P450相互作用的研究进展

细胞色素P450（CYP450）是体内参与药物代谢的重要酶系,其活性在受到诱导或抑制后将干扰药物的作用。植物成分普遍存在于食物与药物中,与CYP450的相互作用将产生广泛影响。总结近年来植物成分与细胞色素P450的7个亚型CYP1A2、CYP2A6、CYP2C9、CYP2C19、CYP2D6、CYP2E1、CYP3A4相互作用的研究结果,为临床上合理用药提供参考。     

中草药对肝细胞色素P450的作用

细胞色素P450（CYP450）是肝微粒体混合功能氧化酶中最重要的一族，据献报道它可被许多化合物诱导或抑制，但有关中草药对CYP450影响作用的研究尚不多见报导。本课题的目的是要筛选几种有潜力的、临床上经常应用的、毒副作用小的中药，采用体内实验和体外实验两种手段来评价中药对细胞色素P450的影响。     

黄酮类化合物的生物活性

黄酮类化合物来源广泛，毒副反应少，多数有广泛的生物活性。影响多种酶活性是其作用广泛性的基础。还影响免疫及炎症细胞的分泌过程和有丝分裂、清除氧自由基、减少自体活性物质的产生和抑制多种病源微生物等。本文就黄酮类化合物生物活性作一综述，为该类物质的开发提供较为系统的基础知识。     

白藜芦醇的药理活性及作用机制

介绍二苯乙烯类化合物白藜芦醇的药理学活性及作用机制。该化合物因能抑制环氧化酶的活性，影响一氧化氮的合成，抑制细胞色素P450，诱导细胞凋亡以及具激素样活性，所以具有较高的临床使用价值。     

细胞色素P450 CYP2E1酶构型特征及其表达调控机制的研究进展

细胞色素P450CYP2E1酶参与代谢活化及失活多种前毒物、前致癌物和少数药物。在细胞色素P450超家族中,CYP2E1具有易介导自由基生成引发氧化应激反应的特征。CYP2E1表达水平可能是机体对环境和工业毒物或致癌物敏感程度的重要因素。研究表明,CYP2E1可被多种内、外源性物质所调控,并且CYP2E1的药理和毒理学功能与其以蛋白构型为基础的代谢行为密切相关。本文综述了CYP2E1基因多态性、酶构型特征与其代谢活性间的关系,并分析了其区别于其他细胞色素P450亚型的表达调控机制。     

以咖啡因为代谢探针测定细胞色素P450 CYP2A6活性

细胞色素P450CYP2A6（CYP2A6）是体内重要的药物代谢酶之一，主要在肝脏表达，约占肝脏细胞色素P450酶的5％。CYP2A6参与抗肿瘤药（环磷酰胺和异环磷酰胺）、麻醉药（氟烷和甲氧氟烷）、前致癌物（黄曲霉素B1、亚硝胺盐等）、环境化合物（汽油醚）及烟草中尼古丁的代谢。CYP2A6活性与这些物质的疗效或毒性以及一些肿瘤的易感性密切相关，测定CY1Y2A6活性有助于预测药物疗效、预防药物毒副反应及肿瘤病因调查。     

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…     

Effects of hydroxyl group numbers on the B-ring of 5,7-dihydroxyflavones on the differential inhibition of human CYP 1A and CYP1B1 enzymes

Flavonoids are polyphenols composed of two aromatic rings (A, B) and a heterocyclic ring (C). In order to determine the effects of the number of hydroxyl groups in the B-ring of the flavonoids on human cytochrome P450 (CYP) 1 family enzymes, we evaluated the inhibition of CYP1A-dependent 7-ethoxyresorufin omicron-deethylation activity by chrysin, apigenin and luteolin, using bacterial membranes that co-express human CYP1A1, CYP1A2, or CYP1B1 with human NADPH-cytochrome P450 reductase. Chrysin, which possesses no hydroxyl groups in its B-ring, exhibited the most pronounced inhibitory effects on CYP1A2-dependent EROD activity, followed by apigenin and luteolin. On the contrary, CYP1A1-mediated EROD activity was most potently inhibited by luteolin, which is characterized by two hydroxyl groups in its B-ring, followed by apigenin and chrysin. However, all of the 5,7-dihydroxyflavones were determined to similarly inhibit CYP1B1 activity. Chrysin, apigenin, and luteolin exhibited a mixed-type mode of inhibition with regard to CYP1A2, CYP1B1, and CYP1A1, with apparent Ki values of 2.4, 0.5, and 2.0 microM, respectively. These findings suggested that the number of hydroxyl groups in the B-ring of 5,7-dihydroxyflavone might have some influence on the degree to which CYP1A enzymes were inhibited, but not on the degree to which CYP1B1 enzymes were inhibited.     

The use of a high-volume screening procedure to assess the effects of dietary flavonoids on human cyp1a1 expression.

We examined the effects of several agents, including dietary flavonoids, on CYP1A1 expression utilizing a recently developed high-throughput screening system for assessing human cytochrome P450 (CYP) induction. HepG2 cells, stably integrated with regulatory regions of human CYP1A1, were treated with resveratrol, apigenin, curcumin, kaempferol, green tea extract (GTE), (-)-epigallocatechin gallate (EGCG), quercetin, and naringenin. Of these flavonoids, resveratrol produced the greatest increase in CYP1A1-mediated luciferase activity (10-fold), whereas GTE, apigenin, curcumin, and kaempferol produced 2- to 3-fold increases in activity. Compared with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), omeprazole, or benzanthracene, where increases in luciferase activity ranged from 12- to 35-fold, these flavonoids exhibited weak agonist activity. The remaining compounds, EGCG, quercetin, and naringenin, produced negligible effects. Cotreatment of cells with TCDD and GTE, naringenin, and apigenin resulted in 58, 77, and 74% reductions, respectively, in TCDD-mediated CYP1A1 induction, indicating that these flavonoids exhibit potential antagonist activity toward the aryl hydrocarbon (Ah) receptor. Furthermore, results also suggest that GTE and apigenin possess Ah receptor antagonist and weak agonist activities. Thus, we have shown that a 96-well plate assay allowing high-throughput screening for P450 induction in less than 24 h was efficient in determining the effects of flavonoids on human CYP1A expression. Signal-to-noise ratios were low, and well-to-well and replicate variability was below 10%, allowing induction to be easily detected in this system. These features illustrate the reliability and feasibility of this high-volume screening system for identifying CYP inducers. Furthermore, results produced with the stable cell line were corroborated in HepG2 cells and primary cultures of human hepatocytes, suggesting that stably integrated cell lines harboring enhancer elements of P450 genes may be highly conducive to high-throughput screening.     

Inhibition of the human liver microsomal and human cytochrome P450 1A2 and 3A4 metabolism of estradiol by deployment-related and other chemicals.

Cytochromes P450 (P450s) are major catalysts in the metabolism of xenobiotics and endogenous substrates such as estradiol (E2). It has previously been shown that E2 is predominantly metabolized in humans by CYP1A2 and CYP3A4 with 2-hydroxyestradiol (2-OHE2) the major metabolite. This study examines effects of deployment-related and other chemicals on E2 metabolism by human liver microsomes (HLM) and individual P450 isoforms. Kinetic studies using HLM, CYP3A4, and CYP1A2 showed similar affinities (Km) for E2 with respect to 2-OHE2 production. Vmax and CLint values for HLM are 0.32 nmol/min/mg protein and 7.5 microl/min/mg protein; those for CYP3A4 are 6.9 nmol/min/nmol P450 and 291 microl/min/nmol P450; and those for CYP1A2 are 17.4 nmol/min/nmol P450 and 633 microl/min/nmol P450. Phenotyped HLM use showed that individuals with high levels of CYP1A2 and CYP3A4 have the greatest potential to metabolize E2. Preincubation of HLM with a variety of chemicals, including those used in military deployments, resulted in varying levels of inhibition of E2 metabolism. The greatest inhibition was observed with organophosphorus compounds, including chlorpyrifos and fonofos, with up to 80% inhibition for 2-OHE2 production. Carbaryl, a carbamate pesticide, and naphthalene, a jet fuel component, inhibited ca. 40% of E2 metabolism. Preincubation of CYP1A2 with chlorpyrifos, fonofos, carbaryl, or naphthalene resulted in 96, 59, 84, and 87% inhibition of E2 metabolism, respectively. Preincubation of CYP3A4 with chlorpyrifos, fonofos, deltamethrin, or permethrin resulted in 94, 87, 58, and 37% inhibition of E2 metabolism. Chlorpyrifos inhibition of E2 metabolism is shown to be irreversible.     

Ephedra water decoction and cough tablets containing ephedra and liquorice induce CYP1A2 but not CYP2E1 hepatic enzymes in rats

1. Ephedra water decoction (EWD) and cough tablets containing ephedra and liquorice (maxing cough tablets, MXCT) have been widely used in the treatment of asthma. In the clinic, EWD and MXCT may be prescribed with theophylline, one of the most popular antiasthmatic drugs. CYP1A2 and CYP2E1 are mainly involved in the oxidative metabolism of theophylline in human liver. Drug interactions involving the cytochrome P450 (CYP) isoforms generally are of two types: enzyme induction or enzyme inhibition. Enzyme inhibition reduces metabolism, whereas induction can increase it.

2. To evaluate the pretreatment effect of EWD and MXCT on CYP1A2 and CYP2E1, CYP1A2 and CYP2E1 activity, the protein expression and mRNA expression levels were determined. After pretreatment with EWD or MXCT, the enzyme activity, mRNA expression and protein expression of CYP1A2 were increased significantly (p?<?0.05), but enzyme activity of CYP2E1 did not change compared with the control.

3. It was demonstrated that EWD or MXCT pretreatment obviously induced CYP1A2, therefore, in patients taking EWD or MXCT, possible CYP-induced drug interaction should be noted to decrease the risk of therapeutic failure or adverse effects resulting from the use of additional therapeutic agents.     

细胞色素P450酶诱导/抑制的研究方法及在药物研究中的应用

细胞色素P450(CYP450)在外源及内源物质的生物转化过程中发挥着至关重要的作用,是肝脏中重要的药物代谢酶。CYP450酶活性/含量的改变直接影响了经其代谢的药物在体内的有效量和作用时间,与药效和用药安全性有密切的联系。因此,了解药物对CYP450酶可能存在的诱导或抑制作用是药物研究过程中不可缺少的研究内容。本文综述了近年来研究CYP450酶诱导/抑制水平和机制的试验方法以及在药物、尤其是在天然产物研究中的应用。