CYP450氧化还原酶的遗传多态对药物代谢的影响

CYP450氧化还原酶(cytochrome P450 oxidoreductase,POR)是所有肝微粒体的细胞色素P450氧化酶(cytochrome P450 monooxygenases,CYP)的唯一电子供体,其中一些CYP是I相药物代谢酶,负责临床上超过80%药物的氧化代谢。另外,POR直接介导了一些抗肿瘤前体药物的代谢。因此,POR的遗传多态引起其活性的改变,对临床药物代谢具有非常重要的临床意义。该文总结了近年来POR的遗传多态影响药物代谢的最新研究进展。     

Multiple oxidants in cytochrome P450 catalyzed reactions: implications for drug metabolism

The activation of molecular oxygen by Cytochromes P450 to the ultimate mono-oxygen oxidant species involves three distinct dioxygen species coordinated to the heme iron. These intermediates have different chemical properties, and have recently been proposed to participate in some Cytochrome P450-catalyzed oxidation reactions. This article reviews the extent of our current knowledge on the roles proposed for the heme- peroxo, hydroperoxo, and superoxo complexes in various reactions. The extent to which such species contribute to the breadth of reactions catalyzed by Cytochrome P450 has yet to be defined, and more definitive experiments are needed to establish such species in the reactions they are proposed to effect.     

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.     

Implications of cytochrome P450 genetic polymorphisms on the toxicity of antitumor agents

In the treatment of cancer, a narrow therapeutic window generally exists between toxicity and suboptimal therapy. In addition, interindividual variation in drug metabolism seriously complicates therapy. Genetic polymorphisms in phase 1 and phase 2 enzymes are present in the population and may explain part of the observed interindividual variation in drug pharmacokinetics. For the cytochrome P450 superfamily, information on variant alleles encoding enzymes with decreased activity is rapidly on the increase. The potential of applying pharmacogenetic screening before therapy in the treatment of cancer seems to be greatest for CYP2B6 (cyclophosphamide treatment), CYP2C8 (paclitaxel therapy), and CYP3A5; however, the drugs of interest still need to be identified for this latter enzyme.     

Mechanistic studies on the drug metabolism and toxicity originating from cytochromes P450

Abstract

Cytochromes P450 are oxidizing enzymes; a few families of cytochromes P450 are implicated in drug metabolism. These enzymatic reactions involve many processes including (i) prodrug to drug conversion, (ii) easy excretion of drug, (iii) generation of reactive metabolites, many of which cause toxicity. In this review, the fundamental biochemical mechanisms associated with the conversion of drugs into the useful or toxic metabolites have been discussed. The mechanisms can be established with the help of many experimental methods like mass spectral analysis, NMR and in vitro analysis etc. Computational methods provide detailed atomic level information, which is generally not available from experimental studies. Thus, the in silico efforts in elucidating the molecular mechanisms are complementary to the known experimental methods and are often clearer (especially in providing 3D information about the metabolites and their reactions). Quantum chemical methods and molecular docking become especially very useful. This review includes five case studies, which explain how the atomic level details were obtained to explore the reaction mechanisms of drug metabolism by cytochromes P450.     

Cytochrome P450 3A: genetic polymorphisms and inter-ethnic differences

Ethnicity is a demographic variable that plays an important role in interindividual variability of drug metabolism and response. The genetic variations of drug-metabolizing enzymes exhibiting interindividual differences of drug metabolism also show differences between populations. The reason for this is that the frequency of a polymorphism is found to differ between populations. The other reason is that different variants are seen in different populations. Most drugs are biotransformed in the body by cytochrome P450. The CYP3A isozymes are responsible for the metabolism of 50-60% of all currently prescribed drugs. Studies have shown that there is variability in CYP3A activity and also inter-ethnic differences in CYP3A-mediated drug metabolism. The purpose of this review is to focus on the genetic polymorphism and ethnic variations in CYP3A-mediated oxidative drug metabolism.     

Human drug metabolising cytochrome P450 enzymes: properties and polymorphisms

The cytochrome P450s are responsible for about 75% of phase I dependent drug metabolism and for the metabolism of a huge amount of dietary constituents and endogenous chemicals. The human has 59 active genes, and 6 of those encode important drug metabolising enzymes. About 40% of cytochrome P450 dependent drug metabolism is catalysed by polymorphic enzymes and such drug P450 interactions are frequently seen in adverse drug reaction reports. In this contribution an update of human cytochrome P450 enzymology and pharmacogenetics is given with particular emphasis on CYP1B1, CYP2B6, CYP2E1 and CYP3As.     

Genetic polymorphisms of cytochrome P450 enzymes and antidepressant metabolism

INTRODUCTION: The cytochrome P450 (CYP) enzymes are the major enzymes responsible for Phase I reactions in the metabolism of several substances, including antidepressant medications. Thus, it has been hypothesized that variants in the CYP network may influence antidepressant efficacy and safety. Nonetheless, data on this field are still contradictory. The authors aim to give an overview of the published studies analyzing the influence of CYP highly polymorphic loci on antidepressant treatment in order to translate the acquired knowledge to a clinical level. AREAS COVERED: The authors collected and compared experimental works and reviews published from the 1980s to the present and included in the Medline database. The included studies pertain to the effects of CYP gene polymorphisms on antidepressant pharmacokinetic parameters and clinical outcomes (response and drug-related adverse effects), with a focus on applications in clinical practice. The authors focused mainly on in vivo studies in humans (patients or healthy volunteers). EXPERT OPINION: Great variability in antidepressant metabolism among individuals has been demonstrated. Thus, with the current interest in individualized medicine, several genetic tests to detect CYP variants have been produced. They provide a potentially useful way to anticipate some clinical outcomes of antidepressant treatment, although they will only be extensively used in clinical practice if precise and specific treatment options and guidelines based on genetic tests can be provided.     

Modelling human cytochromes P450 for evaluating drug metabolism: an update

Cytochrome P450 (CYP) enzymes represent the major catalysts for the Phase 1 metabolism of drugs and other xenobiotics in Mammalia, including Homo sapiens. There is considerable current interest in evaluating and, consequently, predicting the metabolic fate of new chemical entities (NCEs) via modelling molecular interactions with P450 constructs, such that sites of metabolism, particular CYP involvement and binding affinities, can be estimated. This paper focuses on the principles for homology modelling of typical enzyme-substrate interactions within the putative active sites of major P450s associated with drug metabolism in man. It also represents an update on previously published work in this journal /1/.     

细胞色素P450与药物代谢的研究现状

细胞色素P450(CYP)在众多中西药物代谢中起着非常重要的作用。本文综述了与药物代谢相关的CYP亚型、CYP与药物相互作用的关系及中药对CYP的影响，旨在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。同时选择适当的药物作为探针来评价CYP的活性，为实现临床个体化给药提供科学依据。     

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。     

Studying cytochrome P450 kinetics in drug metabolism

BACKGROUND: Determination of cytochrome P450 enzyme-mediated kinetics in vitro can be useful for predicting drug dosing and clearance in humans. Expressed P450s, human liver microsomes, human hepatocytes (both fresh and cryopreserved), and human liver slices are used to estimate K(m) and V(max) values for determination of intrinsic clearance of the drug for scale-up to predict in vivo clearance. OBJECTIVE: To describe the advantages and disadvantages of the various in vitro systems used to estimate kinetic parameters for disposition of drugs and the various kinetic profiles that can be observed. METHODS: A review of the literature was conducted to evaluate the utility of the various in vitro preparations, the methods for determining kinetic parameters and the types of kinetic profiles that may be observed. RESULTS/CONCLUSIONS: The choice of in vitro system for determining kinetic parameters will depend on the objective of the studies, as each system has advantages and disadvantages. Kinetic parameter determinations must be carefully assessed to assure that the correct kinetic model is applied and the most accurate kinetic parameters are determined.     

Monoclonal antibodies and multifunctional cytochrome P450: drug metabolism as paradigm

Monoclonal antibodies are reagents par excellence for analyzing the role of individual cytochrome P450 isoforms in multifunctional biological activities catalyzed by cytochrome P450 enzymes. The precision and utility of the monoclonal antibodies have heretofore been applied primarily to studies of human drug metabolism. The unique and precise specificity and high inhibitory activity toward individual cytochrome P450s make the monoclonal antibodies extraordinary tools for identifying and quantifying the role of each P450 isoform in the metabolism of a drug or nondrug xenobiotic. The monoclonal antibodies identify drugs metabolized by individual, several, or polymorphic P450s. A comprehensive collection of monoclonal antibodies has been isolated to human P450s: 1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C family, 2C19, 2D6, 2E1, 3A4/5, and 2J2. The monoclonal antibodies can also be used for identifying drugs and/or metabolites useful as markers for in vivo phenotyping. Clinical identification of a patient's phenotype, coupled with precise knowledge of a drug's metabolism, should lead to a reduction of adverse drug reactions and improved drug therapeutics, thereby promoting advances in drug discovery.     

The role of human cytochrome P450 enzymes in the metabolism of anticancer agents: implications for drug interactions.

1. Little information is available about the pharmacokinetic interactions of anticancer drugs in man. However, clinically significant drug interactions do occur in cancer chemotherapy, and it is likely that important interactions have not been recognized. 2. Specific cytochrome P450 (CYP) enzymes have been recently shown to be involved in the metabolism of several essential anticancer agents. In particular, enzymes of the CYP3A subfamily play a role in the metabolism of many anticancer drugs, including epipodophyllotoxins, ifosphamide, tamoxifen, taxol and vinca alkaloids. CYP3A4 has been shown to catalyse the activation of the prodrug ifosphamide, raising the possibility that ifosphamide could be activated in tumour tissues containing this enzyme. 3. As examples of recently found, clinically significant interactions, cyclosporin considerably increases plasma doxorubicin and etoposide concentrations. Although cyclosporin and calcium channel blockers may influence the pharmacokinetics of certain anticancer agents by inhibiting their CYP3A mediated metabolism, it is more likely that these P-glycoprotein inhibitors inhibit P-glycoprotein mediated drug elimination. 4. Appropriate caution should be exercised when combining P-glycoprotein inhibitors and potential CYP3A inhibitors with cancer chemotherapy.     

Genetic polymorphisms of human flavin-containing monooxygenase 3: implications for drug metabolism and clinical perspectives

Flavin-containing monooxygenase 3 (FMO3) is a hepatic microsomal enzyme that oxidizes a host of drugs, xenobiotics and other chemicals. Numerous variants in the gene encoding FMO3 have been identified, some of which result in altered enzymatic activity and, consequently, altered substrate metabolism. Studies also implicate individual and ethnic differences in the frequency of FMO3 polymorphisms. In addition, new variants continue to be identified with potentially important clinical implications. For example, the role of FMO3 variants in the pathophysiology of gastrointestinal diseases is an evolving area of research. Two commonly occurring polymorphisms of FMO3, E158K and E308G, have been associated with a reduction in polyp burden in patients with familial adenomatous polyposis who were treated with sulindac sulfide, an FMO3 substrate. These findings suggest a potential role for prospective genotyping of common FMO3 polymorphisms in the treatment of disease states that involve the use of drugs metabolized by FMO3. This review summarizes the current state of research on the genetic polymorphisms of FMO3, with a focus on their clinical implications in gastrointestinal diseases.