P450酶和转运体的DNA甲基化调控：提示药物反应的个体差异

细胞色素P450酶和转运体的基因多态性已被公认是导致临床上药物反应个体差异的重要原因,但个体间某些代谢酶、转运体的基因型和表型不一致的现象不能完全用基因多态性来解释。表观遗传药理学从表观遗传学的角度来研究遗传因素与药物治疗的关系,为药物反应的个体差异提供了新的解释。P450酶和转运体都受表观遗传因素控制。最常见表观遗传调控机制是DNA甲基化,它不会改变基因的遗传代码,而影响基因的表达。由于它对基因组序列的维护,DNA甲基化可用来解释某些基因多态性与表型的不一致现象。本综述总结了DNA甲基化表观遗传调控机制对P450酶和转运体的基因表达影响的最新进展。     

高血压表观遗传药理学研究进展

伴随着遗传药理学的发展,人们逐渐认识到基因多态性不能完全解释降压药物疗效的个体差异。在分子水平上,高血压药物相关代谢酶、受体、转运体都受到基因表达调控的影响,并在降压疗效差异中起着重要的作用。因此,从表观遗传学的角度研究遗传因素与降压药物之间的关系,将有助于更好地解释临床上药物反应产生的个体差异。本文综述总结了DNA甲基化、组蛋白修饰和microRNAS等表观遗传调控方式对高血压相关药物编码基因的影响。     

DNA甲基化与药物效应的表观遗传药理学研究进展

除遗传多态性外,DNA序列的表观遗传修饰,也可造成基因表达水平的改变,从而影响个体对药物的反应,造成药物效应的个体差异。表观遗传药理学研究整个环境因素对药物的影响,为临床药物效应的个体差异提供了新的作用机制学说。DNA甲基化是表观遗传修饰的主要机制之一,本文综述了DNA甲基化对药物效应的影响及环境因素对DNA甲基化的影响。     

临床个体化用药中的药物基因组学考虑

虽然引起药物反应个体差异的原因很多,但遗传因素起相当重要的作用。药物代谢酶、转运药物的蛋白质、受体和其它药物靶体的遗传多态性与药物效应、毒性的个体差异密切相关。药物基因组学是利用已知的基因组学理论,研究遗传因素对药物反应的影响,即研究药物动力学和药效学差异的基因特征,以及基因变异所致的不同个体对药物的不同反应。深入研究遗传因素与临床合理用药之间的重要关系,确定引起个体对药物处置和疗效差异的遗传学特征,将为个体化合理用药提供强有力的科学依据。本文简要介绍药物在血浆中结合的蛋白质的基因多态性和与高血压相关的药物基因组学在临床个体化合理用药中的意义。     

抗癫痫药基因多态性研究进展

临床医学上一致认为药物的基因多态性对于抗癫痫药的个体差异有着重要的意义,基因多态性导致个体出现不同的药理和毒理作用。遗传药理学是一门遗传学学科,随着人们对遗传药理学的深入研究,个体化用药有了新的局面。本文首先分析了抗癫痫药的种类及其疗效,然后详细介绍了当前基因多态性对抗癫痫药疗效研究进展。     

帕金森病药物治疗的遗传药理学研究进展

帕金森病是中老龄人中常见的神经退行性疾病,主要以拟多巴胺类药物治疗为主,但药物反应个体差异较大。与多巴胺代谢相关基因的遗传变异是导致药物反应个体差异的重要原因之一。目前国内研究主要集中在遗传多态性与帕金森病易感性之间的关系方面,而对帕金森病治疗的遗传药理学研究相对较少。该文对多巴胺转运体、多巴胺代谢酶和作用的受体等相关基因的遗传多态性与帕金森病治疗反应个体差异相关性方面的研究进行了一个较为全面的阐述。     

药物依赖中的遗传因素

药物滥用作为一种复杂的行为疾病,它受社会环境因素和个体遗传因素的综合作用。近年来研究发现药物依赖在动物身上存在着种间差异,个体差异以及杂交动物中的差异;临床上也观察到相同环境只有部分人发生药物依赖,并且不同个体对同一药物的体验,耐受性,敏感性,成瘾时间以及戒断反应都不尽一致;对家族的调查,孪生子的研究和收养子研究以及现代分子生物学研究都表明遗传因素在药物依赖上起一定的作用,并且研究已发现某些特定的基因与药物依赖有关。本文回顾了在药物依赖上遗传学的研究进展,阐述了药物依赖遗传学上的研究方法,展望了今后的研究方…     

细胞色素P450基因多态性对心血管药物疗效的影响

基因多态性对药物疗效的影响主要表现在药物代谢酶的多态性、药物受体的多态性和药物靶标的多态性,其中药物代谢酶的基因多态性是导致相同药物、相同剂量、不同个体差异的一个重要生物学因素。遗传药理学（pharmacogenetics）即是从基因水平揭示个体的遗传特质对酶活性、受体蛋白和药物靶标的影响,从基因水平阐释药物效应差异的原因,以及各种基因表型与药物疗效、毒副反应之间的关系。     

药物转运体表观遗传调控机制的研究进展

药物转运体在体内药物吸收、分布和排泄过程中发挥着重要的作用。转运体在各组织器官的分布和表达受到表观遗传修饰调控,导致某些药物体内处置过程出现明显的个体差异。随着表观遗传学的发展,基于表观遗传修饰（如DNA甲基化、组蛋白修饰、microRNA干预等）调控药物转运体的相关研究越来越多。对表观遗传调控药物转运体研究进行综述。     

遗传药理学在临床安全用药中的作用

本文介绍了个体遗传多态性以及遗传药理学在安全用药中的作用。加深对药理效应和药物代谢个体差异的遗传因素及个体化用药的了解,从而提高临床疗效,减少药物不良反应。     

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.     

Role of OATP transporters in the disposition of drugs

During recent years, it has become increasingly recognized that drug transporters play important roles in drug absorption and disposition. Organic anion transporting polypeptides (OATPs) are membrane transporters critically involved in the cellular uptake of drugs in tissues important for pharmacokinetics, such as the intestine, liver and kidneys. Recent advances in the pharmacogenomics of OATP1B1 have revealed that OATP transporters can play important roles in explaining interindividual variability in drug pharmacokinetics, and thus contribute to interindividual as well as interethnic variability in drug response. This article will provide an up-to-date review of human OATPs and their substrates, and a current compilation of their DNA sequence variations.     

Advances in pharmacogenetics and pharmacogenomics

Large differences among normal human subjects in the efficacy and safety of many therapeutic agents are caused by genetically controlled polymorphisms of drug-metabolizing enzymes, drug transporters, and drug receptors. Development of pharmacogenomics as a new field has accelerated progress in pharmacogenetics by elucidating at the level of the human genome the inherited basis for those large interindividual variations. Examples discussed in this review illustrate how this approach can be used not only to guide new drug discovery but also to individualize therapy. Adverse drug reactions, often attributable to large differences among subjects in drug response, constitute a leading cause of death in the USA. Such high morbidity and mortality could be reduced by application of the principles of pharmacogenetics and pharmacogenomics, defined broadly as the study of genetically caused variability in drug response.     

The functional consequences of genetic variations in transporter genes encoding human organic anion-transporting polypeptide family members

It is increasingly recognised that uptake transporters of the organic anion-transporting polypeptide (OATP) family play important roles in drug absorption, distribution and excretion. They are expressed in a variety of different tissues, including gut, brain, kidney and liver. Substrates of OATPs include several endogenous substances, such as bile salts and hormones, and drugs such as HMG-CoA reductase inhibitors (e.g., pravastatin), cytotoxic drugs and antibiotics. Recent advances in the pharmacogenetics of OATPs have demonstrated that variations (polymorphisms) in genes encoding human OATPs can explain parts of the interindividual variability in the pharmacokinetics of drugs and, thus, contribute to the interethnic and interindividual variability in drug response. This review focuses on consequences of these genetic variations and summarises in vivo as well as in vitro analyses demonstrating the impact of polymorphisms in genes encoding OATPs on transport and pharmacokinetics of drugs.     

Interplay of pharmacogenetic variations in ABCB1 transporters and cytochrome P450 enzymes

Interindividual variability in oral drug efficacy and toxicity is commonly observed in all therapeutic areas. Importantly, interindividual variability in drug uptake and metabolism can result in poor drug response, adverse drug reactions, or unfavorable drug-drug interaction. One of the common causes of individual variations in drug response is genetic variation of drug transporters and metabolizing enzymes. Pharmacogenetics are rapidly elucidating the inherited nature of these differences in drug disposition and effects, thereby providing a stronger scientific basis for optimizing drug therapy on the basis of each patient’s genetic constitution. Knowledge of the genotype-phenotype correlation and frequency distribution of functional single nucleotide polymorphisms may be a valuable tool for individualizing drug therapy. This information can also be useful for explaining inter-individual and inter-ethnic variations in drug response and/or adverse effects. In this review, we focus on the interplay between efflux transporter (ATP-binding cassette, sub-family B (MDR/TAP), member 1/ABCB1) and cytochrome P450s according to genetic polymorphism.     

CYP2S1 gene polymorphisms in a Korean population

Cytochrome P450 2S1 (CYP2S1) is a drug-metabolizing enzyme that shows interindividual variations in response to treatments for psoriasis and is regarded as a putative prognostic marker for colorectal cancer treatment. To gain insight into the genetic basis for the interindividual variations, CYP2S1 gene polymorphisms were analyzed in Korean subjects. Using direct sequencing of the CYP2S1 gene, 12 genetic variations, which included the two novel nonsynonymous mutations CYP2S1 S61N (0.3%) and CYP2S1 L230R (0.8%), were identified in 50 Korean subjects. Homology modeling predicted the location of the L230R change to be near two conserved alpha-helices in the hood of the substrate-binding site. Linkage disequilibrium (LD) analysis with seven common CYP2S1 variations showed two discrete LD blocks in CYP2S1 gene and consequently a limited number of haplotypes. Although the importance of novel CYP2S1 variants and haplotypes remains to be discovered, CYP2S1 polymorphisms would provide useful information on interindividual variations with respect to CYP2S1 function, which facilitates drug response predictions and disease prognosis.     

Preclinical factors affecting the interindividual variability in the clearance of the investigational anti-cancer drug 5,6-dimethylxanthenone-4-acetic acid

Cancer chemotherapy is characterized by significant interindividual variations in systemic clearance, therapeutic response, and toxicity. These variations are due mainly to genetic factors, leading to alterations in drug metabolism and/or target proteins. The aim of this study was to determine, using a human liver bank (N=14), the interindividual variations in the expression and activity of liver enzymes that metabolize the investigational anticancer drug 5,6-dimethylxanthenone-4-acetic acid (DMXAA), i.e cytochrome P450 (CYP1A2) and uridine diphosphate glucuronosyltransferase (UGT1A9/2B7). In addition, interindividual variations in enzyme inhibition, hydrolysis of DMXAA acyl glucuronide (DMXAA-G) by plasma and hepatic microsomes, and the binding of DMXAA by plasma proteins also were examined. The results indicated that there was approximately one order of magnitude of interindividual variation in the expression of CYP1A2 and UGT2B7, activity of the enzymes toward DMXAA, and inhibition potency (IC(50)) by diclofenac, cyproheptadine, and alpha-naphthoflavone. The enzyme activities toward DMXAA and IC(50) values were closely correlated with enzyme expression. There was a smaller (2- to 3-fold) variation in the enzyme-catalyzed hydrolysis of DMXAA acyl glucuronide in human plasma and liver microsomes (N=6) and in the binding of DMXAA by plasma proteins in humans. In conclusion, the interindividual variability of DMXAA disposition observed in vitro might reflect the greater elimination variability (>one order of magnitude) in Phase I cancer patients. The variability in DMXAA clearance in these cancer patients would be due mainly to differences in its metabolism and its metabolic inhibition by co-administered drugs. To a lesser extent, variability in the clearance of DMXAA could be due to the hydrolysis of its acyl glucuronide and/or its binding to plasma proteins. Further study is needed to examine the genotype-phenotype relationship, and the result, together with therapeutic drug monitoring may provide a useful strategy for optimizing DMXAA treatment.     

Pharmacogenomics of the OATP and OAT families

Drug disposition is highly dependent on the interplay between drug metabolism and transport in organs such as the intestine, kidney, and liver. Genetically determined variation in drug transporter function or expression is now increasingly recognized to have a significant role as a determinant of intersubject variability in drug response. Similar to the discoveries of functional genetic variations in drug efflux transporters, such as multi-drug resistance proteins 1 and 2, there have been considerable advances in the identification of single nucleotide polymorphisms in transporters that facilitate cellular drug uptake. Among the uptake transporters, members of the organic anion-transporting polypeptides and organic anion transporters can mediate the cellular uptake of a large number of structurally divergent compounds. Accordingly, functionally relevant polymorphisms in these transporters may contribute to interindividual and interethnic variability in drug disposition and response. In this review, recent progress relating to pharmacogenomics of organic anion transporters will be outlined along with a compilation of currently known genetic polymorphisms.     

Genetic basis of drug metabolism.

The application of pharmacogenetics in identifying single nucleotide polymorphisms (SNPs) in DNA sequences that cause clinically significant alterations in drug-metabolizing enzyme activities is discussed. Recent advances in pharmacogenomic research have begun to elucidate the inherited nature of interindividual differences in drug-induced adverse reactions, toxicity, and therapeutic responses. In one particular area of study, variations in DNA sequences (i.e., genetic polymorphisms) explain some of the variability in drug-metabolizing enzyme activities which contribute to alterations in drug clearance and impact patients' response to drug therapy. Historical and current examples of several extensively studied SNPs include the genes encoding for glucose-6-phosphate dehydrogenase, N-acetyltransferase, and the superfamily of cytochrome P-450 (CYP) isoenzymes. Because CYP isoenzymes metabolize a large number of structurally diverse drugs and chemicals, most of the variant genotypes of the CYP2D6, CYP2C9, CYP2C19, and CYP3A families have been identified and studied. Individuals with aberrant genes for these enzymes may experience diminished efficacy or increased toxicity in response to certain drugs because of the different levels of activities associated with variant genotypes. The frequency of variant alleles for drug-metabolizing enzymes often differs among ethnic groups. Continued research in pharmacogenetics will further our understanding in interindividual differences in drug disposition. The application of this knowledge will ultimately help individualize drug dosing and drug therapy selection, predict toxicity or therapeutic failure, and improve clinical outcomes. Pharmacogenetics has elucidated the genetic basis for interindividual variability in drug response and will continue to play a key role in defining strategies to optimize drug therapy.