抗HIV/AIDS药 Kaletra

1 有效成份洛匹那韦(lopinavir)和利托那韦(ritonavir)。2 开发与上市厂商(美)Abbott公司研制开发，2000年9月在美国首次注册并上市。3 作用本品为含有两种蛋白酶抑制剂的复方制剂，可与HIV蛋白酶上的活性位点相结合，进而破坏酶的正常功能，最终导致形成不成熟的无感染性的病毒体。本品的抗病毒活性完全归功于洛匹那韦。洛匹那韦经肝细胞色素P450 CYP3A代谢，利托那韦为CYP3A4的强抑制剂，能可逆性地抑制P450，使洛匹那韦的代谢受遏，从而增加洛匹那韦的血浆药物浓度，使之大大超过对多株HIV毒株的抑制浓度，包括对其它蛋白酶抑…     

某院艾滋病住院患者常用中成药与HIV抗病毒药物潜在相互作用分析

摘 要 目的：调查艾滋病住院患者中成药使用情况,并探讨基于细胞色素P450酶(CYP450)以及P糖蛋白（P gp）与HIV抗病毒药物的潜在药物相互作用。方法: 统计2016年1～12月我院艾滋病区中成药使用种类和频度;查阅文献,分析常用中成药或其活性成分对CYP450及P gp活性的影响;归纳一线HIV抗病毒药物对CYP450及P gp的影响;分析中西药潜在相互作用。结果: 艾滋病区2016年DDDs排名前5的中成药分别为痰热清注射液、地榆升白片、注射用血塞通、丹参滴注液、喜炎平注射液;其中,痰热清注射液、丹参滴注液、喜炎平注射液抑制CYP3A4活性,联用可能会增加洛匹那韦、齐多夫定、依非韦伦和奈韦拉平的血药浓度;注射用血塞通抑制P gp底物外排、丹参滴注液降低P gp的表达,与洛匹那韦、齐多夫定、奈韦拉平联用时,可能会影响其转运的过程。结论: 中成药与HIV抗病毒药物的药物相互作用理论上是存在的,临床意义需进一步研究。     

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。     

蛋白酶抑制剂利托那韦、沙奎那韦和印地那韦对细胞色素P450同工酶的不同抑制作用

人类免疫缺陷病毒1型(HIV-1)的3个主要基因编码的多聚蛋白质,其翻译的后加工过程是由细胞或病毒编码的蛋白酶水解完成的。如果这些蛋白酶丧失了活性,就可以产生不成熟的、无传染性的病毒颗粒,所以HIV病毒编码的蛋白酶抑制剂可以起到抗HIV的作用。目前,该类化合物的研究已经得到很大程度的重视。本研究通过体外实验观察了3个HIV蛋白酶抑制剂利托那韦(ritonavir)、沙奎那韦和印地那韦(indinavir)对人肝细胞微粒体中细胞色素同工酶催化代谢的抑制效应。肝微粒体从6名肾移植供者的正常肝脏中制取,细胞色素P450同工酶CYP1A2、CYP2C9、C…     

己烯雌酚对人肝微粒体内CYP3A4和CYP2C9酶的抑制作用

目的:体外实验考察己烯雌酚(DES)对细胞色素P450 3A4(CYP3A4)和细胞色素P450 2C9(CYP2C9)活性的抑制作用,以评佑DES通过抑制这两个重要的细胞色素P450(CYP)亚型而引发药物-药物相互作用的可能性.方法:混合人肝微粒体与不同浓度的DES(或阳性抑制剂),CYP3A4或CYP2C9的探针...     

地塞米松对大鼠肝脏微粒体细胞色素P-450的诱导效应

目的:观察地塞米松(dexamethasone,DEX)对细胞色素P-450(cytochrome P450,CYP450)的诱导效应,并探讨其诱导机制.方法:雄性Wistar大鼠分别以DEX 0,25,50和100mg·kg-1·d-1诱导处理(ip)4d后,测定大鼠肝脏总CYP450含量,CYP3A1,CYP3A2和CYP2B 1/2的mRNA及蛋白的表达水平,肝脏ERD(CYP3A活性),PROD(CYP2B活性)和BROD(总CYP450活性).结果:CYP450含量、ERD、PROD和BROD活性在DEX多次诱导后都有升高.CYP3A1 mRNA表达水平、蛋白含量和酶活性有明显的升高,剂量效应关系明显;CYP3A2蛋白明显升高,但mRNA表达水平却无明显变化.PROD和CYP2B1/2的mRNA表达水平以及总CYP450含量均在50mg·kg-1·d-1剂量组达到最高值.结论:DEX对雄性大鼠主要诱导CYP3A1和CYP3A2两个CYP450成员表达上调,对CYP2B1/2也有一定的诱导作用,其诱导作用主要表现在酶活性、酶蛋白含量和mRNA表达水平的升高.CYP3A1和CYP3A2的诱导方式可能不同.     

橙皮苷对辛伐他汀调脂作用及细胞色素P4503A mRNA表达的影响

目的　研究橙皮苷对辛伐他汀 (simvastatingroup ,SV)调脂作用及CYP450 3AmRNA表达的影响。方法　将Wistar大鼠随机分为 :对照组 (controlgroup)、高脂血症模型组 (modelgroup)、辛伐他汀组 (simvastatingroup ,SVgroup)、低剂量橙皮苷 +辛伐他汀组 (lowdosehesperidin +SV group ,LDHS)、高剂量橙皮苷 +辛伐他汀组 (highdosehesperidin +SV group ,HDHS)。除对照组外 ,余组均饲喂高脂饮食 ,各实验组按 5mg·kg- 1SV灌胃 ,并分别加用不同剂量的橙皮苷。实验 8wk后 ,检测各组大鼠血脂水平 ,肝脏及小肠CYP450 3A基因表达水平。结果　高脂饲养 8wk后 ,模型组TC、TG和LDL C均升高 (P <0 0 1) ;SV组TC、TG和LDL C较模型组降低 (P <0 0 1或P <0 0 5) ;加用橙皮苷后 ,TC和TG均较SV组呈剂量依赖性降低。模型组肝脏CYP450 3AmRNA表达量与对照组比较无统计学意义 (P >0 0 5) ,小肠CYP450 3AmRNA表达量较对照组升高 (P <0 0 5)。使用SV后 ,肝脏CYP450 3AmRNA表达量较模型组有增加趋势 ,小肠表达量增加 (P <0 0 5)。SV与橙皮苷合用后 ,随橙皮苷剂量的加大 ,肝脏及小肠CYP450 3AmR NA的表达呈下降趋势 ,以HDHS组明显 (P <0 0 5)。结论　橙皮苷能增加SV的调脂作用 ,其机制可能与橙皮苷抑制了CYP450 3A基因表达?     

细胞色素P450酶系对喹乙醇诱导的肾细胞凋亡的影响

目的采用体外细胞培养系统,研究肝脏微粒体细胞色素P450同工酶对喹乙醇(OLA)毒性的影响,筛选和确定影响喹乙醇毒性的主要细胞色素P450同工酶,探索CYP450酶系选择性介导OLA-ROS-细胞凋亡途径。方法(1)以体外培养的人类肾小管上皮细胞(HK-2)作为检测OLA致肾小管毒性的细胞模型,以脏微粒体混合酶系(S9)加入到HK-2细胞培养中模拟体内代谢环境,将CYP450同工酶(CYP2D6、NADPH:P450还原酶、CYP2A、CYP3A、CYP2C、CYP2E1和CYP1A1/CYP1A2)的化学抑制剂分别加入培养体系中,造成不同P450同工酶活性抑制状况,通过细胞增殖抑制率(MTT)试验来检测OLA单独染毒或OLA与抑制剂联合染毒情况下的细胞毒性。(2)通过流式细胞仪DCF法检测各CYP450同工酶抑制剂对OLA所致HK-2细胞ROS产生情况的影响,筛选HK-2细胞内影响OLA作用的主要CYP450同工酶,推测其代谢路径。结果 (1)MTT检测发现,OLA+S9+α-萘黄酮组与OLA+S9组之间以及OLA+4-甲基吡唑+S9组与OLA+S9组之间细胞活性差异有统计学意义(P0.05),表明通过抑制CYP4501A酶以及CPY2E1活性可以使OLA的细胞毒性减轻。(2)OLA能够呈剂量依赖性的诱发细胞内ROS含量升高,且加入CYP1A抑制剂以及CPY2E1抑制剂后,可显著减少HK-2细胞ROS的产生量。结论 OLA通过CYP1A和CYP2E1的代谢诱导HK-2细胞生成ROS,进而可能诱发HK-2细胞的凋亡产生细胞毒性和肾毒性。     

CYP450在SAP组织中的表达及对临床治疗的指导意义

目的:研究急性重症胰腺炎(SAP)模型中CYP450(细胞色素P450)在组织中的表达及对临床治疗的指导意义.方法:以3%牛磺胆酸钠逆行胰胆管注射制备鼠SAP模型,检测血清淀粉酶,采用免疫组织化学方法分别对雄性SD大鼠SAP制备模型术后4 h、12 h及正常对照组标本中CYP450的表达进行检测.结果:CYP450主要表达于胞浆,SAP模型组空肠、肝脏组织中的CYP450表达均明显高于正常对照组(P＜0.001).结论:CYP450在大鼠SAP中表达显著增强,提示其在SAP的疾病发展及临床治疗中都具有重要意义.     

奈玛特韦/利托那韦与阿托伐他汀合用致肌酸激酶和转氨酶升高1例

<正>2021年由美国辉瑞公司研发的奈玛特韦/利托那韦片(Nirmatrelvir/ritonavir,Paxlovid)上市,其可将轻度或中度的新型冠状病毒(Corona virus disease 2019,COVID-19)患者的住院或是死亡风险降低约89%^[1]。由于奈玛特韦/利托那韦可抑制细胞色素P450 3A4酶(Cytochrome P4503A4,CYP3A4),与多种药物合并用药存在一定的相互作用。现通过对1例长期规律服用阿托伐他汀钙片的女性新冠患者在服用奈玛特韦片/利托那韦片后,出现肌酸激酶和转氨酶的轻度升高的病历进行讨论。     

Diversity and substrate specificity in the structures of steroidogenic cytochrome P450 enzymes

Mammalian cytochrome P450 (CYP) comprise a large group of enzymes that play many important roles in the biosynthesis of steroid hormones and vitamins. In addition, they participate in the metabolism of drugs and xenobiotics. All known mammalian CYP enzymes are membrane-associated proteins, which complicated their X-ray crystallographic analysis. In recent years, however, significant progress has been made in the X-ray crystallographic analysis of mammalian CYP enzymes involved in the steroid hormone and vitamin D(3) metabolism. The knowledge from three-dimensional structures of mammalian CYP enzymes will benefit drug discovery and development.     

Characterization of the cytochrome P-450 gene family responsible for the N-dealkylation of the ergot alkaloid CQA 206-291 in humans.

The ergot alkaloid CQA 206-291 (CQA) was converted by human liver microsomes (n = 16) almost exclusively to the N-deethylated metabolite (I), as identified by the on-line coupling of liquid chromatography and mass spectroscopy. Metabolite I formation exhibited monophasic and linear enzyme kinetics (2.9-300 microM), and a 5.6-fold interindividual variability (7.2-40.2 nmol/mg/hr). Chemical inhibition experiments revealed that imidazole antimycotic agents (ketoconazole, miconazole, and clotrimazole) were potent inhibitors of this N-deethylation. Polymorphically metabolized substrates (sparteine and phenytoin), well-established cytochrome P-450 probe substrates (antipyrine and tolbutamide), and steroid hormones (estradiol and testosterone) were noninhibitory, indicating that their metabolism is catalyzed by forms of cytochrome P-450 that do not catalyze this route of CQA biotransformation. The ergot alkaloids--dihydroergotamine, bromocriptine, and SDZ 208-911--were competitive inhibitors of metabolite I formation, suggesting that these compounds are metabolized by similar enzymes. Cyclosporine A was a potent competitive inhibitor of CQA metabolism, providing initial evidence that formation of metabolite I was catalyzed by proteins of the CYP3 gene family. This was substantiated by the finding that CQA metabolism was completely inhibited by a polyclonal antibody directed against a pregnenolone 16 alpha-carbonitrile-inducible cytochrome P-450 of rat liver. The rate of CQA metabolism correlated significantly to the level of CYP3A4 expression, the rate of cyclosporine A metabolism to each of the primary metabolites (M-1, M-17, and M-21), and the rate of midazolam 4-hydroxylation. COS 1 cells transfected with human CYP3A4 and CYP3A5 provided direct evidence that these enzymes catalyze the metabolism of CQA.(ABSTRACT TRUNCATED AT 250 WORDS)     

57 varieties: the human cytochromes P450

The human cytochrome P450 (CYP) complement of heme-thiolate enzymes is reviewed. Of the 57 individual P450s characterized in Homo sapiens thus far, it is apparent that approximately one-half are associated with the metabolism of drugs and other xenobiotics, whereas the other half have endogenous functions in steroid, prostanoid, eicosanoid and fatty acid metabolism. This review covers the extent of enzyme functionality for the known human P450s, focusing primarily on their role in the Phase I metabolism of foreign compounds, which involves the CYP1, CYP2 and CYP3 families.     

Human cytochrome p450 family 4 enzymes: function, genetic variation and regulation

The microsomal cytochrome P450 (CYP) family 4 monooxygenases are the major fatty acid omega-hydroxylases. These enzymes remove excess free fatty acids to prevent lipotoxicity, catabolize leukotrienes and prostanoids, and also produce bioactive metabolites from arachidonic acid omega-hydroxylation. In addition to endogenous substrates, recent evidence indicates that CYP4 monooxygenases can also metabolize xenobiotics, including therapeutic drugs. This review focuses on human CYP4 enzymes and updates current knowledge concerning catalytic activity profiles, genetic variation and regulation of expression. Comparative differences between the human and rodent CYP4 enzymes regarding catalytic function and conditional expression are also discussed.     

Selective dehydrogenation/oxygenation of 3-methylindole by cytochrome p450 enzymes.

3-Methylindole (3 MI) is a selective pulmonary toxicant, and cytochrome P450 (P450) bioactivation of 3 MI, through hydroxylation, epoxidation, or dehydrogenation pathways, is a prerequisite for toxicity. CYP2F1 and CYP2F3 exclusively catalyze the dehydrogenation of 3 MI to 3-methyleneindolenine, without detectable formation of the hydroxylation or epoxidation products. It was not known whether 3 MI is simply an excellent dehydrogenation substrate for all P450 enzymes, or whether certain cytochrome P450s responsible for 3 MI bioactivation have unique active sites that only catalyze the dehydrogenation of the molecule, while other P450s would catalyze only the oxygenation of 3 MI. Therefore, the kinetics of product formation by the CYP2F1 and CYP2F3 enzymes were compared with other cytochrome P450 enzymes. The enzymes tested were CYP1A1, CYP1A2, CYP1B1, and CYP2E1. The CYP1A1 and CYP1A2 enzymes produced all three 3 MI metabolites: the dehydrogenation product, 3-methyleneindolenine (V(max)/K(m) = 4 and 22, respectively); the hydroxylation product, indole-3-carbinol (V(max)/K(m) = 42 and 100, respectively); and the epoxidation product, 3-methyloxindole (V(max)/K(m) = 4 and 72, respectively). These CYP1A enzymes catalyzed oxygenation of 3 MI at much faster rates than dehydrogenation. CYP1B1 produced indole-3-carbinol (V(max)/K(m) = 85) and 3-methyloxindole (V(max)/K(m) = 7), and CYP2E1 only produced 3-methyloxindole (V(max)/K(m) = 98), but neither enzyme catalyzed the formation of the dehydrogenated product. Six additional P450 enzymes that were tested formed none of the dehydrogenation product. The ability of the various CYP1 family enzymes to catalyze the formation of all three major 3 MI metabolites, along with the specific oxygenation by CYP2E1, illustrates that dehydrogenation of 3 MI is not a substrate-directed process, but that the members of the CYP2F family possess unique active sites that specifically catalyze only the dehydrogenation mechanism.     

Human Cytochrome P450 Family 4 Enzymes: Function,Genetic Variation and Regulation

The microsomal cytochrome P450 (CYP) family 4 monooxygenases are the major fatty acid ω-hydroxylases. These enzymes remove excess free fatty acids to prevent lipotoxicity, catabolize leukotrienes and prostanoids, and also produce bioactive metabolites from arachidonic acid ω-hydroxylation. In addition to endogenous substrates, recent evidence indicates that CYP4 monooxygenases can also metabolize xenobiotics, including therapeutic drugs. This review focuses on human CYP4 enzymes and updates current knowledge concerning catalytic activity profiles, genetic variation and regulation of expression. Comparative differences between the human and rodent CYP4 enzymes regarding catalytic function and conditional expression are also discussed.     

P-糖蛋白与CYP450酶对千金子肠道毒性的影响

P-糖蛋白和细胞色素CYP450酶为体内重要的转运蛋白和代谢酶,参与药物在体内的吸收和代谢。千金子对胃肠道有强烈的刺激作用,可以产生峻泻,本文将从P-糖蛋白和CYP450酶功能着手分析二者对千金子肠道毒性的影响,为千金子肠道毒性的研究提供新的思路和方法。     

CYP2D6基因多态性及对药物代谢的影响

CYP2D6代谢酶是细胞色素P450家族中的成员之一,是参与Ⅰ相代谢和众多内源性物质和不同药物消除的酶。虽然它在肝脏中的含量大约只占肝脏总量的2%,但在临床上却参与了25%以上的常用药物的代谢活动。在所有参与药物代谢的细胞色素P450基因家族中,CYP2D6是唯一不能被诱导的酶,这种酶具有广泛的多态性,这种多态性对酶的药物代谢功能具有重要影响,CYP2D6的这种多态性和药物代谢功能所表现的对个体活性的差异,在遗传药理学上具有重要意义。本文从CYP2D6基因多态性和它对药物代谢的影响这两方面进行了阐述。