次黄苷三磷酸焦磷酸酶遗传多态性对硫嘌呤类药物疗效和不良反应影响的研究进展

硫嘌呤类药物作为一类常用的免疫抑制剂,广泛应用于临床.然而其治疗窗窄,药动学个体差异大一直是困扰该类药物临床应用的难题.尽管硫嘌呤甲基转移酶（thiopurine methyltransferase,TPMT）基因多态性被认为是影响硫嘌呤类药物药动学的主要遗传因素,但研究结论并不统一.而最近的一些研究将焦点集中到了次黄苷三磷酸焦磷酸酶（inosine triphosphate pyrophosphatase,ITPA）的遗传多态性上.因此,本文就ITPA遗传多态性对硫嘌呤类药物疗效和毒性影响的研究进展作一综述,以期为临床个体化应用硫嘌呤类药物提供理论指导.     

TPMT遗传多态性对硫嘌呤类药物疗效和毒性影响的研究进展

目的:总结硫嘌呤甲基转移酶(TPMT)遗传多态性对硫嘌呤类药物疗效和毒性影响的研究进展,为该药的个体化应用提供参考。方法:通过检索Pub Med和相关专业学术期刊全文数据库近10年来有关TPMT遗传多态性对硫嘌呤类药物疗效和毒性影响的研究文献,对TPMT遗传药理学研究进展作一整理归纳。结果和结论:TPMT是被研究得最早也是最多的一个硫嘌呤类药物代谢酶。TPMT遗传多态性和酶活性的个体差异可以部分解释患者服用硫嘌呤类药物后疗效和不良反应的不同。但目前其与硫嘌呤类药物所致的不良反应之间的关系尚没有统一的结论。对于TPMT遗传多态性对硫嘌呤类药物个体化应用的影响有待于多中心大样本的前瞻性研究以证实。     

瑞苏伐他汀遗传药理学研究进展

胆固醇水平升高是动脉粥样硬化发病的主要原因。瑞苏伐他汀为临床常用的抑制胆固醇合成的药物,其药动学和药效学存在显著个体差异。药物转运体、药物代谢酶、药物靶点的遗传多态性对瑞苏伐他汀的体内代谢和临床疗效个体差异具有重要作用。本文阐述了药物转运体、细胞色素P450酶和其他相关基因的遗传多态性对瑞苏伐他汀药动学和药效学的影响,为临床制定个体化用药方案提供参考。     

硫嘌呤类药物遗传药理学研究进展

临床上硫嘌呤类药物应用广泛,但在此类药物的使用过程中,血液毒性、肝脏毒性、胰腺炎等不良反应的发生率较高。研究发现,硫嘌呤甲基转移酶(thiopurine S-methyltransferase,TPMT)的活性和遗传多态性,以及三磷酸肌苷焦磷酸酶(inosine triphosphate pyrophosphatase,ITPA)的遗传多态性与硫嘌呤类药物不良反应的发生密切相关。本文综述了TPMT活性和基因多态性,以及ITPA基因多态性的研究进展。     

影响硫嘌呤类药物个体化应用的相关转运体遗传多态性的研究状况

硫嘌呤类药物作为一类常用的免疫抑制剂,其疗效和不良反应的差异与转运体的基因多态性的关系已成为研究热点,本文收集并分析了相关转运体的遗传多态性与硫嘌呤类药物疗效和不良反应的相关性报道,以期为临床硫嘌呤类药物个体化应用提供一定参考。     

基因多态性对巯嘌呤类药物作用影响的研究进展

基因多态性是影响巯嘌呤类药物在体内代谢,最终造成药物疗效和毒性差异的主要原因。近年来研究发现,单一药物代谢酶或转运体的基因多态性与巯嘌呤类药物临床不良反应不完全相关,而多基因分析可能更好地解释患者对该药的不耐受原因。本文介绍了多种与巯嘌呤类药物有关的酶基因多态性的研究情况,同时就其代谢特点及与该药敏感性的关系进行综述。     

丙戊酸钠基因组学的研究进展

丙戊酸钠是临床常用广谱抗癫痫药物。该药治疗窗窄、代谢个体差异大,体内代谢受多种因素影响,其中,药物代谢酶的遗传多态性是影响该药代谢的重要因素。通过查阅相关文献,总结了基因组学对丙戊酸钠临床用药的影响,为丙戊酸钠临床个体化给药提供参考。     

硫嘌呤甲基转移酶分子机制研究进展

硫嘌呤甲基转移酶（TPMT）在硫嘌呤类药物的体内代谢中起着关键作用，其活性水平与药物效应及毒副作用密切相关。TPMT活性具有遗传多态性和种族差异。TPMT酶活性降低或缺乏与其基因突变密切相关。对TPMT遗传多态性分子基础的研究具有重要意义。本文综述有关TPMT基因表达调控和TPMT基因突变的分子机制的研究进展。     

细胞色素P_(450)3A5基因多态性的研究进展

细胞色素P4503A5（Cytochrome P4503A5，CYP3A5）是CYP3A亚族中的一种重要的同工酶。其遗传多态性影响着许多经CYP3A介导的药物，如地尔硫革、阿芬太尼等在肝微粒体中的氧化代谢，该酶的活性存在明显的个体差异，对不同个体的药物治疗作用和不良反应及药物的毒性产生重要影响，是引起个体及种族间对同一底物代谢能力不同的原因之一。本文主要对CYP3A5基因多态性及其种族差异，CYP3A5基因多态性对药物处置、药动学、药效学及疾病风险等影响进行综述如下。     

心血管药物代谢酶及其遗传药理学研究进展

目的:为心血管药物的临床合理应用和个体化给药提供参考。方法:检索近年来国内、外遗传药理学和药物基因组学在心血管药物代谢酶研究方面的论文,对其进行分析、归纳和总结。结果与结论:药物代谢酶的基因多态性是心血管药物疗效和不良反应产生个体差异的重要原因,是个体化给药的依据。     

药物代谢中的药酶特性与临床研究近况

目的:为了促进药物代谢酶在临床上的深入研究。方法:以近几年国内外大量有代表性的论文为依据进行分析、归纳、整理。结果:药物代谢酶大多具有遗传多态性,其活性受相关药物影响,遗传多态性和药物之间代谢性相互作用是临床药物反应千变万化的重要因素。结论:药物代谢酶的认识和研究有助于临床合理用药和减少药物不良反应。     

口服降糖药的遗传药理学研究进展

糖尿病是一种受多基因和环境因素共同影响的代谢性疾病。药物代谢酶、受体和转运体的遗传多态性对口服降糖药的体内代谢和降糖疗效有重要作用。本文从细胞色素P450酶、转运体和受体多态性方面对5种主要口服降糖药（磺脲类、噻唑烷二酮类、氯茴苯酸类、双胍类、α-葡萄糖甙酶抑制剂）的体内代谢和药物效应的影响作一综述。     

新型抗癫痫药物奥卡西平基因多态性研究进展

奥卡西平是癫痫部分性发作和全面强直阵挛性发作的首选药物之一,是卡马西平的一种10-酮类衍生物,其耐受性好且不良反应少。然而,临床研究表明奥卡西平在相同群体的不同个体和不同群体之间呈现出显著差异,其中遗传因素起到重要作用。本文通过收集近年来国内外有关奥卡西平代谢酶、转运体、药效靶蛋白以及不良反应方面有关基因多态性的文献报道,进一步明确其对奥卡西平血药浓度、疗效及不良反应的影响,为临床个体化治疗提供参考。     

基因多态性对钙离子通道阴滞剂类抗高血压药物药动学及疗效的影响

钙离子通道阻滞剂是常用的一种高血压治疗药物,其中又以二氢吡啶类钙离子通道阻滞剂为主要代表,常见的有硝苯地平、氨氯地平、非洛地平等。然而,不同的患者个体对此类抗高血压药物可产生不同的降压效果,这种差异是环境和遗传共同作用的结果。基因多态性决定了药物代谢酶、转运体以及作用受体的差异,是导致药物疗效差异的重要原因之一。综述药物代谢酶、转运体和作用受体的基因多态性对钙离子通道阻滞剂类抗高血压药物的药动学和疗效的影响。     

麻醉药及其辅助药物基因组学的研究进展

临床上麻醉药及其辅助药物治疗的个体化差异备受关注。目前,越来越多的研究着重于麻醉药物与转运蛋白、作用靶受体和代谢酶的基因多态性之间的关系．并发现麻醉药物效应与相关基因多态性存在密切联系。本文就近年来麻醉药及其辅助药物基因组学的研究进展作一综述。     

药物代谢酶遗传多态性对药物神经毒性的影响

神经毒性是药物常见的毒性反应之一。神经系统对药物引起的损害尤其敏感,药物引起神经系统结构和功能的微小改变即可表现出严重的精神或行为异常,因此药物引起的神经毒性越来越得到人们的关注。药物引起的神经毒性存在个体差异,其中遗传因素对这种差异的产生发挥重要作用。药物代谢酶影响药物体内的生物转化过程,因此代谢酶的遗传多态性在一定程度上决定了不同个体对药物神经毒性的易感性。本篇综述将着重探讨药物代谢酶中的细胞色素P450酶、谷胱甘肽转移酶和N-乙酰转移酶遗传多态性对药物神经毒性易感性的影响。     

Pharmacogenetics and immunosuppressor drugs: impact and clinical interest in transplantation

The domain of solid organ transplantation is characterized by the use of variable drug combinations with drug-drug interactions, and the presence of two genomes, that of the transplanted organ and that of the receiver, which can be involved in the pharmacogenetics of these drugs. This paper is a literature review of the impact of the genetic polymorphisms of the metabolic enzymes, efflux transporters and therapeutic targets of the main immunosuppressive drugs (cyclosporine, tacrolimus, sirolimus and mycophenolate) on the dose-concentration and concentration-effect relationships of these drugs. The polymorphisms of metabolic enzymes have significant effects on the pharmacokinetics of all these drugs, but the clinical trials for validating treatment individualization based on these genetic differences are still lacking. It should be noted that the influence of the donor's genome has seldom been studied and has been found to be significant in liver transplant recipients. The influence of efflux transporter genes polymorphisms, in particular of P-glycoprotein and MPR2, is controversial. As for the polymorphisms of the drug targets genes, either they have not been reported (calcineurin, mTOR), or their influence has only been the subject of a few preliminary studies (IMPDH2). The pharmacogenetics of immunosuppressants is thus still an open field for investigations and potential therapeutic progress.     

Molecular genetics of cancer susceptibility

Studies on the role of genetically polymorphic enzymes like cytochrome P450 1A1, arylamine N-acetyltransferase 2 or glutathione S-transferase M1 as cancer susceptibility factors date back more than 20 years, and some associations have been confirmed in several studies and meta-analyses. Overall, the extent of risk modulation due to these polymorphisms is only moderate but remains epidemiologically relevant. The role of some of these polymorphisms in human health may even be ambiguous: rapid acetylation, for example, protects from urinary bladder cancer but appears to increase the risk of laryngeal, lung and colon cancer. The first genetic polymorphisms in xenobiotics transporters such as P-gp (MDR1) and MRP2 have recently been identified. These polymorphisms may have great impact as cancer susceptibility factors as well as factors modulating the outcome of cancer treatment. Enzymes involved in generation or detoxification of reactive oxygen species also have to be considered; one of these enzymes, myeloperoxidase, constitutes a relatively strong lung cancer risk factor, as confirmed in 4 independent studies. Other genes, including those coding for DNA repair enzymes, signal transduction and cell growth regulation, may ultimately prove more important than the metabolic enzymes as cancer susceptibility factors. Study designs in molecular genetic epidemiology are evolving; large ongoing prospective trials increasingly allow confirmatory nested case control studies to be performed. However, carefully controlled, large case-control studies will remain the mainstay in molecular genetic epidemiology. Molecular genetic epidemiological evaluation of response to chemoprevention as well as response to the adverse events of cancer chemotherapy are likely to provide results that may be useful for individualized prevention and treatment in the near future. Since routine genotyping of all persons is now feasible, something like a genotype passport may soon become reality, and molecular and clinical epidemiological studies will have to provide the basis for understanding how to use genotype data for the benefit of the population.     

Pharmacogenomics of tamoxifen: roles of drug metabolizing enzymes and transporters

Tamoxifen has been widely used for the prevention of recurrence in patients with hormone receptor-positive breast cancer. Tamoxifen requires metabolic activation by cytochrome P450 (CYP) enzymes for formation of active metabolites, 4-hydroxytamoxifen and endoxifen, which have 30- to 100-fold greater affinity to the estrogen receptor and the potency to suppress estrogen-dependent breast cancer cell proliferation. CYP2D6 is a key enzyme in this metabolic activation and it has been suggested that the genetic polymorphisms of CYP2D6 influence the plasma concentrations of active tamoxifen metabolites and clinical outcomes for breast cancer patients treated with tamoxifen. The genetic polymorphisms in the other drug-metabolizing enzymes, including other CYP isoforms, sulfotransferases and UDP-glucuronosyltransferases might contribute to individual differences in the tamoxifen metabolism and clinical outcome of tamoxifen therapy although their contributions would be small. Recently, involvement of a drug transporter in the disposition of active tamoxifen metabolites was identified. The genetic polymorphisms of transporter genes have the potential to improve the prediction of clinical outcome for the treatment of hormone receptor-positive breast cancer. This review summarizes current knowledge on the roles of polymorphisms in the drug-metabolizing enzymes and transporters in tamoxifen pharmacogenomics.