细胞色素P450酶基因多态性的研究进展及临床意义

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,体现在个体对于各种化合物的代谢存在明显差异。本文综述了CYP的基因多态性、与药物代谢相关的CYP各亚型的特点和临床意义,主要目的是合理解释和预测临床上药物间相互作用和药物不良反应等,为实现临床个体化给药提供科学依据。     

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。     

细胞色素P4502D6基因多态性和药物相互作用

细胞色素P4502D6（CYP2D6）是一种重要的P450系氧化代谢酶,参与多种重要药物的代谢.CYP2D6具有基因多态性,对药物的代谢呈现明显的个体差异.而且CYP2D6能被多种药物竞争性抑制和诱导,药物联用时易产生相互作用.本文从CYP2D6的基因多态性与代谢表型、底物竞争作用、代谢酶的诱导和抑制等方面,探讨CYP2D6基因多态性与药物相互作用的关系.     

人肝脏细胞色素P450 2B6催化药物生物转化研究进展

CYP 2B6是细胞色素P450 2B亚家族中的主要成员,参与催化多种内源、外源化合物,特别是多种临床药物的生物转化.本文综述了CYP 2B6的表达、催化药物生物转化及基因多态性的研究进展.     

外源物对细胞色素P450同工酶表达的基因调控

细胞色素P450（CYP450）酶系中的1,2,3,4家族是代谢外来化合物的主要酶系。外源物进入体内,因其代谢活性的不同以及CYP450各家族敏感程度的差异,使CYP450的活性和表达受到不同程度的影响。近年来,可通过分子诊断学（如分子探针等）实验方法鉴定受影响的CYP450同工酶的种类,并精确了解外源物在代谢过程中对CYP450的调控方式。本文从的物在CYP450基因水平上的调节（包括对DNA、转录、mRNA及蛋白质合成水平的影响）和芳烃受体（AhR)对CYP450基因的调节等方面进行了综述。CYP450同工酶的存在类型及表达水平可直接影响机体对外源物的代谢转化,这与环境致癌物、化学毒物、药物等外源物对机体的致癌风险、中毒反应及药物间相互作用密切相关。对CYP450同工酶的合理调控将对防治疾病、维护人类健康有重要意义。     

细胞色素P450表达的诱导机制及其筛选方法的研究进展

细胞色素P450(CYP450)是药物和其他内、外源物的主要代谢酶，其活性受到某些药物的诱导或抑制，引起临床用药中的相互作用。CYP450诱导方式有五种，即芳香烃受体介导型、乙醇型、过氧化物酶体增殖剂激活受体介导型、组成型雄甾烷受体介导型和孕烷X受体介导型。除乙醇型诱导是通过稳定酶蛋白以外，其余都由核受体介导。CYP3A是最重要的药物代谢酶，诱导CPY3A4是造成临床药物间相互作用的首要原因。本文综述了CYP450诱导机制的研究进展，介绍了3种快速筛选药物CYP3A诱导活性的新方法，并阐明了其对新药评价的重要意义。     

CYP2C基因多态性对药物代谢的影响

编码药物代谢酶、运载体或靶受体的基因多态性能够影响许多药物的生物转化和临床效果，尤其是对治疗指数较窄的药物影响显著。细胞色素氧化酶P450（CYP450）在外源性物质包括药物、环境化合物和内源性物质如类固醇激素、花生四烯酸等的代谢中起重要作用。我们综述了CYP2C基因多态性与药物代谢的关系，以期能够作为临床医师合理用药的依据，从而降低药物不良反应，     

细胞色素P450基因多态性与药物代谢研究进展

细胞色素P450酶(cytochrome P450,CYP450)是参与人类药物代谢过程的重要酶,在肝细胞和小肠上皮细胞的光滑内质网中含量丰富,其主要功能是氧化还原各种内源性物质和外源性物质。CYP450酶参与80%目前应用药物的I相代谢,参与各种激素合成,影响与激素相关的肿瘤疾病发展。CYP450基因和表型存在高度多态性,体现在个体对于各种物质的代谢存在明显差异。本文综述了CYP450的基因多态性、与药物代谢相关的CYP450各亚型特点和临床意义,对发展以指导个体化用药为基础的精准医学具有重要意义。     

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。     

细胞色素P_(450)2C9基因多态性与药物相互作用

目的:为指导临床合理用药、实现个体化给药提供参考。方法:本文从CYP2C9的基因多态性与代谢表型、代谢底物、代谢酶的诱导和抑制等方面,探讨CYP2C9基因多态性与药物相互作用的关系。结果与结论:CYP2C9作为一种重要的P450系氧化代谢酶,具有基因多态性,参与多种药物的氧化代谢,能被多种药物竞争性抑制,这是造成药物作用个体差异的最重要因素之一,也是发生药物相互作用的原因之一。因此对其研究具有非常重要的临床意义。     

Expression of CYP3A4 and CYP3A7 in Human Foetal Tissues and its Correlation with Nuclear Receptors

Previous reports have suggested that the nuclear receptors vitamin D receptor (VDR), peroxisome proliferator‐activated receptor α (PPARα), pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are involved in the regulation of the drug‐metabolizing enzyme cytochrome P450 (CYP) 3A4 expression in adults. The aim of this study was to investigate the gene expression of CYP3A4 and the foetal CYP3A7 in human foetal tissues and their relation to gene expression and genetic variations in the nuclear receptors VDR, PPARα, PXR and CAR. We determined the relative expression of CYP3A4 and CYP3A7 and these nuclear receptors in foetal livers, intestines and adrenals, using quantitative PCR. In addition, the expression of these enzymes was also analysed in adult liver. There was a high interindividual variability in CYP3A4 and CYP3A7, 49 times and 326 times, respectively. Both CYP3A4 and CYP3A7 had the highest expression in the liver. There were significant correlations (p < 0.001) between the nuclear receptors studied and the expression of CYP3A4 and CYP3A7 in foetal liver, as well as the expression of CYP3A4 in foetal intestine. Polymorphisms in the VDR gene, rs1544410 and rs1523130 (TaqI), in the PXR gene, rs1523130, and in the PPARα gene, rs4253728, were not correlated with CYP3A4 or CYP3A7 expression. However, C‐homozygous individuals of the TaqI VDR polymorphism had 60% lower VDR gene expression (p < 0.05), than individuals carrying one or two T alleles. In conclusion, differences in the expression of nuclear receptors might determine the variability in CYP3A4 and CYP3A7 expression observed in foetal liver.     

Relevance and limits of pharmacogenetics to detect patients at risk of adverse drug reactions

For more than 15 years genetic polymorphism of drug metabolism has been extensively studied. Poor Metabolizer (PM) and Extensive Metabolizer (EM) Slow Acetylators (SA) Rapid Acetylators (RA) phenotype and genotype can be defined for CYP2D6 (Debrisoquine) and N-AT (acetylation). Lists of drugs whose metabolism is CYP2D6 or N-AT dependent have been published. So it is theoretically possible to forecast an adverse drug reaction (ADR) for a specific patient who is given a drug affected by a polymorphism. However, not only PM are at risk of ADRs. When an active or reactive metabolite is produced, EM might be at risk whatever the enzyme involved. Drug interactions must also be taken into account. Competitive inhibition of the metabolism of a drug CYP2D6 dependent provokes not only a blurring effect on phenotyping, leading to a misclassification, but also increases the risk of ADRs. New drug metabolic polymorphism is under scrutiny. Determination of phenotypes and genotypes when possible, development of investigations of drug metabolic capacity at large, in patients exhibiting ADR's, might improve the efficiency of pharmacovigilance to forecast at-risk subjects.     

Impact of P450 genetic polymorphism on the first-pass extraction of cardiovascular and neuroactive drugs

This review highlights the present knowledge on the CYP2D6 (sparteine/debrisoquine) and the CYP2C19 (mephenytoin) polymorphisms. The relevant mutations at genomic level affecting protein expression and function and consequences for first-pass metabolism and effects of cardiovascular and neuroactive drugs are highlighted. In vitro techniques for identification of metabolic steps catalyzed by polymorphic enzymes will be discussed as well as drug-drug interactions related to CYP2D6 and CYP2C19. The importance of the CYP2D6 polymorphism arises from the fact that this enzyme, which is involved in metabolism of more than 50 drugs, is not active in about 8% of a Caucasian population. This group is named poor metabolizers in contrast to the remainder of the population called extensive metabolizers. Depending on the pharmacokinetic and pharmacodynamic properties of the administered drug and its metabolites elevated concentrations of the parent compound can result in an increased risk of toxicity or loss of therapeutic effects in poor metabolizers. On the other hand ultrarapid metabolizers of CYP2D6 might require higher doses than recommended in order to achieve therapeutic drug levels. Moreover, consequences of polymorphic CYP2C19 expression, which is not active in 20% of Orientals and 3% of Caucasians, for drug disposition will be outlined.     

Clinical pharmacokinetics of docetaxel : recent developments

Docetaxel belongs to the class of taxane antineoplastic agents that act by inducing microtubular stability and disrupting the dynamics of the microtubular network. The drug has shown a broad spectrum of antitumour activity in preclinical models as well as clinically, with responses observed in various disease types, including advanced breast cancer and non-small cell lung cancer. The pharmacokinetics and metabolism of docetaxel are extremely complex and have been the subject of intensive investigation in recent years. Docetaxel is subject to extensive metabolic conversion by the cytochrome P450 (CYP) 3A isoenzymes, which results in several pharmacologically inactive oxidation products. Elimination routes of docetaxel are also dependent on the presence of drug-transporting proteins, notably P-glycoprotein, present on the bile canalicular membrane. The various processes mediating drug elimination, either through metabolic breakdown or excretion, impact substantially on interindividual variability in drug handling. Strategies to individualise docetaxel administration schedules based on phenotypic or genotype-dependent differences in CYP3A expression are underway and may ultimately lead to more selective chemotherapeutic use of this agent.     

Tamoxifen cytotoxicity in hepatoblastoma cells stably transfected with human CYP3A4

Tamoxifen can exert its effects through the competitive inhibition of estrogen receptors or other mechanisms. HepG2 cells lacking estrogen receptors and engineered to overexpress CYP3A4, the most important CYP to metabolize the drug, appear to be a good model to study the effects of tamoxifen metabolites. Tamoxifen altered cell cycle of transduced HepG2 cells, decreased G0/G1 cell numbers, diminished proliferation index and induced cell death mostly in cells overexpressing CYP3A4 but was without significant effect on cytotoxicity or proliferation of cells engineered to overexpress CYP2E1 or on empty vector transfected cells. Tamoxifen did not change MDR1 levels irrespectively on CYP450s expression, but inhibited by approximately 50% p-gp functions in all cell types. Drug treatment significantly increased dehydroepiandrosterone sulfotransferase activity and sulfotransferase inhibition significantly decreased tamoxifen cytotoxicity. Our results support the view that metabolic activation of tamoxifen in liver cells may proceed via CYP450-mediated metabolism and subsequent sulfotransferase-mediated activation and point to the role of CYP3A4 and dehydroepiandrosterone sulfotransferase in adverse tamoxifen effects.     

The role of cytochrome P450 pharmacogenomics in chronic non-cancer pain patients

Introduction: Pharmacogenomics is the field that studies an individualized treatment approach for patients’ medication regimen that can impact drug safety, productivity, and personalized health care. Pharmacogenomics characterizes the genetic differences in metabolic pathways which can affect a patient’s individual responses to drug treatments.

Areas covered: The various responses to pharmacological agents are mainly determined by the different types of genetic variants of the CYP450. CYP2D6 polymorphism is well known for its variation in the metabolism of drugs from many therapeutic arenas, including some analgesic drugs such as codeine, hydromorphone, oxycodone and tramadol. Allele combinations determine the phenotypic expression, characterized as either: extensive metabolizer, intermediate metabolizer, ultra-rapid metabolizer and poor metabolizer.

Expert opinion: The Human Genome Project (HGP) revolutionized the future of medicine and the way health care providers approach individualized patient treatment, and chronic pain management is one of those areas. The key findings in the literature appear to be related to the CYP2D6 expression and its high polymorphism influencing the metabolism of opioid medications, and the impact of that on the patient’s therapeutic outcome thus exemplifying the importance of genetic testing for CYP2D6 in the process of physician therapeutic decision making.     

中草药对孕烷X受体和组成型雄烷受体等核受体通路影响的研究进展

孕烷X受体（pregnane X receptor,PXR）是核受体亚家族的成员之一,参与大量的外源性和内源性化学物质的生物转化,能被多种中草药激活,调节下游靶基因的表达,在药物代谢酶和转运体的调节中起重要作用。组成型雄烷受体（constitutive androstane receptor,CAR）和PXR一样能与外源性配体结合调节CYP2B6、CYP3A4、CYP2C19、UGT1A1的表达,共同参与CYP药物代谢酶的调节,成为药物作用的靶标。     

Genetic polymorphism of CYP2A6 in the German population

Genetic polymorphism of drug metabolizing enzymes (DME) can lead to severe toxicity or therapeutic failure of pharmacotherapy. Additionally, genetically determined differences in the activity of the metabolic enzymes can increase an individual's susceptibility to certain types of chemically induced cancers and possibly other diseases. Cytochrome P450 is one of the most important metabolic systems of the organism involved in the oxidation of different xenobiotics. This contribution summarizes and updates the information concerning the genetic polymorphism of the CYP2A6 isoform of the cytochrome P450. A special emphasis is put upon the genotyping techniques of CYP2A6 with a comparative analysis of their predictable sensitivity and specificity given on the example of the German population.