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。     

细胞色素P450酶系及其在药物代谢中的作用

综述了细胞色素P450酶系近年来的研究进展，对P450认识的不断深入，使人们有可能预测药物的相互作用和环境因素对药物代谢的影响     

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酶诱导和抑制效应高通量筛选系统研究进展*

细胞色素P450酶（CYP450）活性的诱导或抑制，是引起临床药物代谢性相互作用的主要作用机制。目前确定候选药物出现此类相互作用可能性的主要方法是通过体外CYP450诱导和抑制潜能的快速筛选。现从CYP450诱导机制、目前发展的综合活性筛选系统和诱导筛选系统、抑制效应筛选系统以及硅上虚拟筛选系统等几个方面，对CYP450诱导和抑制效应高通量筛选系统的研究进展作一综述。     

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。     

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。     

中药有效成分对细胞色素P450影响的研究进展

［摘要］查阅国内外近几年来关于中药有效成分对细胞色素P450酶系影响的文献,结果显示黄酮及黄酮衍生物、香豆素类、生物碱、多糖、皂苷、挥发油等有效成分均可影响其活性。研究中药有效成分对细胞色素P450的影响有利于指导合理用药及新药研发,揭示药物相互作用机制。     

探讨细胞色素P450酶系和药物的代谢情况

在药物代谢过程中细胞色素P450酶系具有十分重要的作用。此类酶主要存在于肝微粒当中,在生物转化过程承担了十分重要的功能。其活性与药物代谢速率具有密切的关联性,甚至可对药物清除产生直接作用。基于上述特点学术界将其作药物代谢过程中的第一相酶。本文对细胞色素P450酶系和药物的代谢进行了分析并对细胞色素P450酶系的作用进行了综合性阐述,提出了相应的观点,供以参考。     

肠道细胞色素P450和P-糖蛋白对口服药物生物利用度的影响

目的综述肠道细胞色素P450和P-糖蛋白(P-gp)对口服药物生物利用度的影响,包括CYP450、Pgp的作用及CYP与Pgp的联合作用。方法收集、阅读并分析近十年来关于肠道细胞CYP450和Pgp影响口服药物生物利用度的文献。结果 CYP450和Pgp在胃肠道均具有高表达,且两者的底物具有显著的重叠性,所以肠道细胞CYP450对已吸收药物的生物转化作用和肠道细胞中Pgp对已吸收药物的主动外排作用是影响口服药物生物利用度的重要因素。结论肠道细胞CYP450和Pgp对药物的口服生物利用度具有重要影响。     

Effects of tebuconazole on cytochrome P450 enzymes,oxidative stress,and endocrine disruption in male rats

The major objective of the present study was to determine the ability of a triazole fungicide tebuconazole to induce cytochrome P450‐dependent monooxygenases, oxidative stress, and endocrine‐disrupting activity using male rats treated with tebuconazole at 10, 25, and 50 mg/kg p.o. once daily for 28 days. In liver, tebuconazole dose‐dependently increased microsomal contents of cytochrome P450 and cytochrome b₅ and the activities of NADPH‐cytochrome P450 reductase, 7‐ethoxyresorufin O‐deethylase, methoxyresorufin O‐demethylase, pentoxyresorufin O‐dealkylase, 7‐ethoxycoumarin O‐deethylase, aniline hydroxylase, and erythromycin N‐demethylase. In kidney, tebuconazole increased 7‐ethoxycoumarin O‐deethylase activity without affecting other monooxygenase activities. In marked contrast to liver and kidney, tebuconazole decreased testicular 7‐ethoxyresorufin O‐deethylase, methoxyresorufin O‐demethylase, 7‐ethoxycoumarin O‐deethylase, aniline hydroxylase, and erythromycin N‐demethylase activities. The results of immunoblot analysis of liver microsomes of controls and tebuconazole‐treated rats revealed that tebuconazole induced CYP1A1/2, CYP2B1/2, CYP2E1, and CYP3A proteins in liver. Additions of tebuconazole to liver microsomes inhibited microsomal 7‐ethoxycoumarin O‐deethylase activity in vitro (IC₅₀ = 1.50–1.69 µM). Treatment of rats with tebuconazole decreased glutathione content and increased glutathione S‐transferase, superoxide dismutase, catalase, and glutathione peroxidase activities in liver; increased superoxide dismutase activities in kidney and testis; but decreased glutathione S‐transferase activity in testis. Treatments with tebuconazole decreased serum testosterone concentration and cauda epididymal sperm count. The present study demonstrates that tebuconazole induces a multiplicity of CYPs and oxidative stress in liver; inhibits testicular P450 and glutathione S‐transferase activities; and produces anti‐androgenic effects in male rats.     

呋喃二烯对肝脏细胞色素P450酶不同亚型的影响

目的 考察呋喃二烯(furanodiene,FDE)对肝脏微粒体主要的细胞色素P450(CYP)酶活性的影响。方法 采用探针底物法,考察FDE在体外孵育体系中对大鼠和人肝微粒体CYP1A、CYP2A、CYP3A、CYP2C、CYP2D、CYP2E1的抑制作用,并计算相应的IC50值;采用微粒体体外“鸡尾酒”孵育法(cocktail法),考察大鼠经低、高剂量FDE(40 mg·kg^-1和160 mg·kg^-1)连续灌胃7 d,其肝微粒体主要CYP酶活性的变化。结果 FDE对大鼠肝微粒体CYP2D1和CYP2C6/7有较弱的抑制作用,其IC50分别为15.8和23.8 μmol·L^-1;对人肝微粒体CYP2C9也有较弱的抑制作用,IC50为26.1 μmol·L^-1。与对照组比较,大鼠灌胃40 mg·kg^-1 FDE,肝微粒体主要CYP酶活性无显著变化;灌胃160 mg·kg^-1后,肝微粒体CYP2E1活性为对照组的164%。结论 FDE对大鼠和人肝微粒体CYP主要亚型的抑制作用较弱;40 mg·kg^-1 FDE对大鼠肝微粒体主要CYP酶未显示明显诱导作用,160 mg·kg^-1 FDE对肝微粒体CYP2E1有一定的诱导作用。     

Cytochrome P450 genotype‐guided drug therapies: An update on current states

Over the past 2 decades, knowledge of the role and clinical value of pharmacogenetic markers has expanded so that individualized pre‐emptive therapy based on genetic background of patients could be within reach for clinical implementation. This is evidenced from the frequent updating of drug labels that incorporates pharmacogenetic information (where compelling data become available) by the regulatory agencies (such as the US FDA), and the periodical publication of guidelines of specific therapeutic recommendations based on the results of pharmacogenetic tests by the pharmacogenetics working groups or consortiums of professional bodies. Clinical relevance of the cytochrome P450 (CYP) polymorphism related to dose, effectiveness and/or toxicity of key drugs are presented in this review, including that of warfarin, clopidogrel, tricyclic antidepressants, and proton pump inhibitors. Prospect for routine clinical application of CYP genotyping before prescribing drugs is still currently unclear due to challenges and barriers associated with availability of well‐defined and validated pharmacogenetic studies, the interpretation, result reporting and potential error of genotype testing, involvement of non‐genetic factors, and other patient's demographic and disease conditions. Further studies to provide additional supporting clinical data and acceleration of pharmacogenetic testing standards and techniques should help improve the evidence base needed for clinical utility and hence move the implementation of genotype‐guided therapy in clinical practice a step closer to reality.     

抗寄生虫化合物9901对犬和人细胞色素CYP450同工酶的作用

通过Beagle犬及人肝微粒体体外试验评价抗寄生虫化合物9901低、中、高剂量（7．5、30和160mg／kg）对肝细胞色素P450同工酶1A2、3A4、2A6512D6的作用。用HPLC法测定非那西丁、睾酮、香豆素和右美沙芬经微粒体酶代谢所得产物的生成量以评价酶活。犬肝微粒体试验结果显示，化合物9901对CYP1A2和CYP3A4无诱导或抑制作用。人肝微粒体体外试验表明，化合物9901浓度小于200μg/L时，对CYP1A2、2A6、2D6和3A4均没有诱导或抑制作用，提示其在联合用药时较安全。     

黄酮类化合物对细胞色素P450 CYP1，2E1，3A4和19的影响

黄酮类化合物广泛存在于蔬菜、坚果、水果和饮料及中草药中，可诱导或抑制多种细胞色素P450的活性。本篇综述主要集中回顾黄酮类化合物对于细胞色素P450 CYP1，2E1，3A4和19的影响。归纳总结了该类物质抑制和诱导细胞色素P450的多种机制，如刺激特定的受体、稳定相关mRNA等。并总结了该类物质对细胞色素P450的影响体内和体外水平的研究结果并非总是一致的原因，如体内外的浓度的差异、基因和其他环境因素的影响。由于黄酮类化合物可通过影响细胞色素P450的活性影响药物代谢从而导致药物不良反应和药物相互作用，因此在将该类物质与其他药物合用时应高度重视。     

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 enzyme activity and protein expression in primary porcine enterocyte and hepatocyte cultures

1. A method for the isolation and cultivation of porcine hepatocytes and porcine duodenal enterocytes for the investigation of drug oxidation reactions has been established. 2. Hepatocytes as well as enterocytes metabolized ethoxyresorufin (EROD) and ethoxycoumarin (ECOD) effectively, the rate being 31 +/- 17 pmol/h dish (EROD) and 9530 +/- 4062 pmol/h dish (ECOD) in the case of hepatocytes, and 9 +/- 4 pmol/h dish (EROD) and 510 +/- 467 pmol/h dish (ECOD) in the case of enterocytes. Diazepam, another CYP monooxygenase substrate, was also metabolized by porcine hepatocytes but not with porcine enterocytes, thus indicating differences in the metabolic competence of the liver and the gut. 3. The ability to induce enzymes responsible for the metabolism of ethoxyresorufin and ethoxycoumarin was investigated in vitro on treatment of the cell cultures with either 50 muM 3-methylcholanthrene (3-MC) or 50 muM beta-naphthoflavone (beta-NF). With enterocyte cultures, ECOD activity was inducible up to 20-fold, whereas EROD remained unchanged following treatment with either 3-MC or beta-NF. 4. Western blotting provided additional evidence for the expression of CYP1A1 and CYP3A4 at the protein level and treatment of cultured enterocytes with 30 muM Aroclor 1254 or 50 muM beta-NF resulted in enhanced expression of the CYP1A protein, and CYP3A4 protein expression was induced following treatment with 50 muM DEX, 2 mM PB, 30 muM Aroclor 1254 or 50 muM beta-NF. 5. The metabolism of diazepam was also investigated with baculovirus-expressed human CYP enzymes (2C8, 2C9-ARG, 2C9-CYS, 2C19, 3A4, 3A4+cytochrome b₅ and 3A5) and evidence was obtained to suggest the formation of temazepam and oxazepam by enzymes of the CYP3A subfamily. Small amounts (32 +/- 12 ng/ml) of desmethyldiazepam were additionally recovered in microsomal preparations of all CYP-transfected cell lines. 6. In conclusion, porcine duodenal enterocytes can successfully be cultured for a short period and may be used as a tool for studying intestinal metabolism, whereas porcine hepatocytes can be cultured for prolonged periods (> 10 days) reliably to investigate hepatic drug oxidation reactions.     

豆腐果苷对人肝微粒体CYP450酶体外抑制作用研究

目的:通过评价豆腐果苷在体外对人肝微粒体CYP450酶的7种亚型酶活性的影响,预测服用豆腐果苷可能出现的食物-药物及药物-药物代谢的影响。方法:将豆腐果苷与CYP450酶7种亚型的特异性探针底物咖啡因(CYP1A2)、右美沙芬(CYP2D6)、甲苯磺丁脲(CYP2C9)、S-美芬妥因(CYP2C19)、氯唑沙宗(CYP2E1)、香豆素(CYP2A6)及咪达唑仑(CYP3A4)与人肝微粒体进行孵育反应,采用HPLC和LC-MS/MS法测定对应的7种代谢产物(1,7-二甲基黄嘌呤、去甲右美沙芬、4-羟基甲苯磺丁脲、4-羟基美芬妥因、6-羟基氯唑沙宗、7-羟基香豆素和1-羟基咪达唑仑)的浓度,与对照组比较,确定豆腐果苷对以上7种亚酶活性的影响。结果:豆腐果苷在1～100μmol.L-1时对7种酶的抑制作用均无明显统计学意义(P>0.05)。结论:豆腐果苷可能不会引起有临床意义的CYP450酶抑制现象的发生。     

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。