有机阴离子转运多肽181的遗传药理学进展

人体存在多种类型的药物转运体,对于药物的吸收、分布和排泄起重要作用。参与药物跨膜转运的转运体功能受影响,将可能导致诸多临床药物的疗效、毒副作用甚至药物相互作用的发生。在各种影响因素中,遗传多态性所起的作用最为重要,可导致基因表达和蛋白功能发生改变。目前,阐明转运体基因的多态性以及基因型与表型之间的相互关系已成为应用遗传信息指导临床个体化用药的必要步骤。本文就肝脏有机阴离子转运多肽1B1（OATP1B1[OATP-C],编码基因SLCO1B1）基因多态性对药代动力学和药效动力学的影响及其临床意义等方面的进展作一综述。     

与 P－糖蛋白及 MDR1基因关联的药物转运研究现状

P－糖蛋白（P－gp）由MDR1基因编码,腺苷三磷酸依赖的药物外向转运蛋白,是介导药物吸收与转运动力学的关键转运体。不少药物通过核因子κB（ NF－κB）和孕烷X受体（ PXR）信号通路直接影响MDR1基因和P－gp的表达,导致P－gp的功能发生改变,从而影响药物的吸收转运。因此,本文对P－gp介导的药物转运相互作用、药物对P－gp和MDR1基因表达的影响,以及与P－gp／MDR1基因表达相关的NF－κB和PXR信号通路的研究概况进行收集与探讨,以期从基因和蛋白水平上,为研究药物吸收转运特征的变化提供一定依据。     

药物转运体有机阴离子转运多肽1B1基因多态性的研究进展

有机阴离子转运多肽1B1(OATP1B1)是肝脏中重要的药物转运通路之一,其遗传多态性可改变药动学参数,影响多种药物在体内的分布,继而影响药效及药物不良反应. 该文对OATP1B1结构与功能,OATP1B1编码基因的结构及多态性对功能的影响,SLCO1B1多态性对他汀类药物的影响,SLCO1B1多态性对口服降糖药的影响,SLCO1B1多态性对抗肿瘤药的影响等进行综述.     

有机阴离子转运多肽1B3的研究进展

有机阴离子转运多肽1B3(organic anion transporting polypeptide 1B3,OATP1B3)属于溶质转运体(solute carrier,SLC)超家族,主要负责将内、外源物质转运至肝细胞代谢。OATP1B3是肝脏特异性转运体,通常局限性地分布于肝细胞窦状隙侧肝细胞膜上,近期研究发现在前列腺癌、结肠癌、肺癌等肿瘤组织和细胞中也存在着高表达。溶质转运体1B3(SLCO1B3)具有明显的基因多态性,334T>G和699G>A单体型可明显影响OATP1B3的转运活性,从而介导药物-药物相互作用的发生,导致临床用药的个体差异。此外,OATP1B3可通过作用于孕烷X受体(pregnane X receptor,PXR)和组成性雄甾烷受体(constitutive androstane receptor,CAR)等核受体配体的转运,影响体内PXR和CAR的转录活性,从而调控药物代谢酶如细胞色素P450 3A4(CYP3A4)的表达。本文将对OATP1B3近年来的研究进展进行综述。     

SLCO1B1基因T521C多态性对氟伐他汀药代动力学、药效学和药物不良反应影响的系统评价北大核心CSCD

目的研究SLCO1B1基因T521C位点多态性与氟伐他汀药物的药代动力学、药效学和药物不良反应的相关性。方法本文采用计算机检索Cochrane Library、Pub Med、EMBase、Webof Science、中国知网和万方数据库,截至2017年12月。收集有关SLCO1B1基因多态性对氟伐他汀影响的研究。筛选文献并对最终纳入的6篇文献进行质量评价和系统综述。结果 SLCO1B1基因T521C位点多态性对服用氟伐他汀后的低密度脂蛋白浓度和总胆固醇降低有显著影响,对氟伐他汀的体内药代动力学过程没有显著影响,且没有证据证明该位点与氟伐他汀导致肌病的药物不良反应有相关性。结论 SLCO1B1基因T521C位点的多态性显著影响氟伐他汀的药效学,与氟伐他汀的药代动力学及药物不良反应的发生无关。     

有机阴离子转运多肽1B1（OATP1B1）基因多态性对他汀类药物影响的研究进展

有机阴离子转运多肽1B1(OATP1B1)是一种负责转运多种内外源性物质进入肝细胞发挥作用的摄入型转运蛋白。他汀类药物又称3-羟基-3-甲基戊二酸单酰辅酶A(HMG-CoA)还原酶抑制剂,临床上广泛应用于调脂及心脑血管疾病的预防,其疗效及不良反应有显著的个体化差异。研究表明OATP1B1基因多态性是导致他汀类药物个体化差异的重要因素。对OATP1B1基因多态性对他汀类药物影响的研究进展进行综述,为他汀类药物的个体化、安全化应用提供可能的理论指导。     

大蒜素对肝脏药物转运体OATP1B1转运功能的影响

目的:观察大蒜素对肝脏药物转运体-有机阴离子转运多肽1Bl(Organic anion transportingpolypeptide 1B1,OATP1B1)转运功能的影响.方法:利用稳定表达人OATP1B1的人胚胎肾293(Human embryonic kidney 293,HEK293)细胞株,以[3H]硫酸雌酮和普伐他汀为底物进行OATP1B1摄取反应,观察大蒜素对OATP1B1摄取功能的影响.结果:大蒜素对OATP1B1摄取[3H]硫酸雌酮和普伐他汀的功能有竞争性抑制作用,抑制常数Ki值分别为(18.3±5.2)μmol/L和(15.4±6.8) μmol/L.结论:大蒜素对肝脏药物转运体OATP1B1转运功能的抑制作用可诱导中药-西药相互作用.     

MDR1基因多态性及其临床相关性

P-糖蛋白作为一种广泛分布于全身各组织和器官的重要转运体,对多种药物在体内的吸收、分布、代谢、排泄过程以及防止有害外源性物质的侵袭起重要作用。作为P-糖蛋白的编码基因,多药耐药基因(multidrug resistance-1,MDR1)的多态性在一定程度上决定了上述过程在个体与个体之间的差异,因此对许多疾病的易感性以及特定药物在体内的药动学,药效学和治疗效应均存在较大影响。本文将对MDR1基因多态性对疾病易感性和临床上药动、药效学过程的影响进行综述。     

有机阴离子转运多肽1B1对2型糖尿病药物治疗的影响

目的:了解有机阴离子转运多肽1B1(OATP1B1)对2型糖尿病药物治疗的影响。方法:查阅近年来国内外相关文献,就OATP1B1的影响机制、对那格列奈和瑞格列奈等药物的影响、其他基因组信息进行归纳和总结。结果:OATP1B1对那格列奈和瑞格列奈的体内过程影响明显,人类OATP1B1编码基因(SLCO1B1)521T>C位点的突变对那格列奈药动学和药效学的影响与野生型对照组比较,差异有统计学意义;OATP1B1对瑞格列奈药动学影响呈剂量依赖关系。SLCO1B1 388A>G位点的突变对2型糖尿病药物的体内过程影响不明显。结论:OATP1B1作为摄入型转运体在糖尿病的药物治疗中起重要作用。患者的基因组信息将成为2型糖尿病患者临床合理用药的重要参考因素,有必要对OATP1B1进行更深入、系统的研究。     

有机阴离子转运多肽1A2基因多态性的研究进展

目的为有机阴离子转运多肽1A2(organic anion transporting polypeptide1A2,OATP1A2)基因多态性的深入研究及临床用药提供参考。方法查阅了国内外相关文献25篇,对其进行了分析和总结。结果 OATP1A2具有明显的基因多态性,516A>C、404A>T等单体型可显著影响OATP1A2的转运活性,-1 105G>A、-1 032G>A等单体型可明显影响药物体内药动学过程,从而导致临床用药的个体差异。结论目前有关OATP1A2基因多态性的研究多基于体外实验研究其不同多态变体转运能力的差异,更多进一步的OATP1A2基因多态性临床相关性研究具有重要意义。     

Genetic polymorphisms of ATP-binding cassette transporters ABCB1 and ABCG2: therapeutic implications

Pharmacogenomics, the study of the influence of genetic factors on drug action, is increasingly important for predicting pharmacokinetics profiles and/or adverse reactions to drugs. Drug transporters, as well as drug metabolism play pivotal roles in determining the pharmacokinetic profiles of drugs and their overall pharmacological effects. There is an increasing number of reports addressing genetic polymorphisms of drug transporters. However, information regarding the functional impact of genetic polymorphisms in drug transporter genes is still limited. Detailed functional analysis in vitro may provide clear insight into the biochemical and therapeutic significance of genetic polymorphisms. This review addresses functional aspects of the genetic polymorphisms of human ATP-binding cassette transporters, ABCB1 and ABCG2, which are critically involved in the pharmacokinetics of drugs.     

Genetic polymorphisms of ATP-binding cassette transporters ABCB1 and ABCG2: therapeutic implications

Pharmacogenomics, the study of the influence of genetic factors on drug action, is increasingly important for predicting pharmacokinetics profiles and/or adverse reactions to drugs. Drug transporters, as well as drug metabolism play pivotal roles in determining the pharmacokinetic profiles of drugs and their overall pharmacological effects. There is an increasing number of reports addressing genetic polymorphisms of drug transporters. However, information regarding the functional impact of genetic polymorphisms in drug transporter genes is still limited. Detailed functional analysis in vitro may provide clear insight into the biochemical and therapeutic significance of genetic polymorphisms. This review addresses functional aspects of the genetic polymorphisms of human ATP-binding cassette transporters, ABCB1 and ABCG2, which are critically involved in the pharmacokinetics of drugs.     

Validation of in vitro cell models used in drug metabolism and transport studies; genotyping of cytochrome P450, phase II enzymes and drug transporter polymorphisms in the human hepatoma (HepG2), ovarian carcinoma (IGROV-1) and colon carcinoma (CaCo-2, LS180) cell lines

Human cell lines are often used for in vitro biotransformation and transport studies of drugs. In vivo, genetic polymorphisms have been identified in drug-metabolizing enzymes and ABC-drug transporters leading to altered enzyme activity, or a change in the inducibility of these enzymes. These genetic polymorphisms could also influence the outcome of studies using human cell lines. Therefore, the aim of our study was to pharmacogenotype four cell lines frequently used in drug metabolism and transport studies, HepG2, IGROV-1, CaCo-2 and LS180, for genetic polymorphisms in biotransformation enzymes and drug transporters. The results indicate that, despite the presence of some genetic polymorphisms, no real effects influencing the activity of metabolizing enzymes or drug transporters in the investigated cell lines are expected. However, this characterization will be an aid in the interpretation of the results of biotransformation and transport studies using these in vitro cell models.     

Genetic polymorphisms of SLCO1B1 for drug pharmacokinetics and its clinical implications

Various drug transporters are selectively expressed in single or multiple tissues, such as the intestine, liver and kidney, where these transporters play various roles in drug absorption, distribution and excretion. Genetic polymorphisms in drug transporters as well as drug-metabolizing enzymes are associated with interindividual differences in drug disposition, efficacy and toxicity. Organic anion transporting polypeptide 1B1 (OATP1B1, gene SLCO1B1) is expressed on the basolateral membrane of hepatocytes and can facilitate hepatic uptake of certain clinically relevant drugs such as statins except for fluvastatin, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, antidiabetic drug (repaglinide) and anticancer drugs (SN-38 and methotrexate). Some single nucleotide polymorphisms or haplotypes of the SLCO1B1 gene have been identified and demonstrated to have functional significance for transporter activity. For examples, the SLCO1B1*15 haplotype (or 521T>C genotype) results in decreased uptake activity of SN-38 from systemic circulation, leading to increased plasma concentration of SN-38 and an enhanced risk of neutropenia. This review focuses on the impact of genetic polymorphisms of the SLCO1B1 gene on transport activity, and implications for the clinical efficacy and toxicity of clinically useful drugs.     

Uptake transporters of the human OATP family: molecular characteristics, substrates, their role in drug-drug interactions, and functional consequences of polymorphisms

Organic anion transporting polypeptides (OATPs, gene family: SLC21/SLCO) mediate the uptake of a broad range of substrates including several widely prescribed drugs into cells. Drug substrates for members of the human OATP family include HMG-CoA-reductase inhibitors (statins), antibiotics, anticancer agents, and cardiac glycosides. OATPs are expressed in a variety of different tissues including brain, intestine, liver, and kidney, suggesting that these uptake transporters are important for drug absorption, distribution, and excretion. Because of their wide tissue distribution and broad substrate spectrum, altered transport kinetics, for example, due to drug-drug interactions or due to the functional consequences of genetic variations (polymorphisms), can contribute to the interindividual variability of drug effects. Therefore, the molecular characteristics of human OATP family members, the role of human OATPs in drug-drug interactions, and the in vitro analysis of the functional consequences of genetic variations in SLCO genes encoding OATP proteins are the focus of this chapter.     

Functional evaluation of ABCB1 (P-glycoprotein) polymorphisms: high-speed screening and structure-activity relationship analyses

Evidence is accumulating to strongly suggest that drug transporters are one of the determinant factors governing the pharmacokinetic profile of drugs. Effort has been made to identify genetic variation in drug transporter genes. In particular, genetic variations of the human ABCB1 (MDR1) gene have been most extensively studied. Hitherto more than fifty single nucleotide polymorphisms (SNPs) and insertion/deletion polymorphisms in the ABCB1 gene have been reported. However, at the present time, information is still limited with respect to the actual effect of those genetic polymorphisms on the function of ABCB1. In this context, we have undertaken functional analyses of ABCB1 polymorphisms. To quantify the impact of genetic polymorphisms on the substrate specificity of ABCB1, we have developed a high-speed screening system and a new structure-activity relationship (SAR) analysis method. This review addresses functional aspects of the genetic polymorphism of ABCB1 and provides the standard method to evaluate the effect of polymorphisms on the function.     

Organic cation transporters and their pharmacokinetic and pharmacodynamic consequences

To clarify the considerable interindividual variability in the pharmacokinetics, efficacy, and toxicity of drugs, genetic polymorphism of drug transporters has attracted interest because these transporters play important roles in the gastrointestinal absorption, biliary and renal elimination, and distribution to target sites of their substrates. Of the over 325 members of the solute carrier superfamily, this review focuses on the molecular features, expressional regulation, and genetic polymorphisms of the organic cation transporter (OCT) family, and the pharmacokinetic or pharmacodynamic consequences for organic cationic drugs. Although the clinical significance is still unclear, many studies have reported the importance of OCTs in the tissue distribution and elimination of their substrates in vitro and in vivo, and the impact of functional non-synonymous single nucleotide polymorphisms or differential expression levels of OCTs on the large interindividual variation in the pharmacokinetics and response of organic cationic drugs such as metformin, imatinib, and cisplatin.     

The genetic polymorphism of drug transporters: functional analysis approaches

Evidence is accumulating to strongly suggest that drug transporters are one of the determining factors governing the pharmacokinetic profile of drugs. To date, a variety of drug transporters have been cloned and classified as solute carriers and ATP-binding cassette transporters. Such drug transporters are expressed in various tissues such as the intestine, brain, liver, and kidney, and play critical roles in the absorption, distribution and excretion of drugs. However, at the present time, information is limited regarding the genetic polymorphism of drug transporters and its impact on their function. In this context, we have undertaken the functional analyses of the polymorphisms identified in drug transporter genes. This article aims to provide an overview on the functional aspects of the non-synonymous polymorphisms of drug transporters and to present standard methods for the evaluation of the effect of polymorphisms on their function.     

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。     

Polymorphisms of MRP1 (ABCC1) and related ATP-dependent drug transporters

Genetic variations in drug metabolizing enzymes and targets are established determinants of adverse drug reactions and interactions, but less is known about the role of genetic polymorphisms in membrane transport proteins. MRP1 (ABCC1) is one of 13 polytopic membrane proteins that comprise the 'C' subfamily of the ATP-binding cassette (ABC) superfamily of transport proteins. MRP1 and related ABCC family members, including MRP2, 3, 4 and 5 (ABCC2, 3, 4 and 5), each have a distinctive pattern of tissue expression and substrate specificity. Together, these five transporters play important roles in the disposition and elimination of drugs and other organic anions, and in maintenance of blood-tissue barriers, as confirmed by enhanced chemosensitivity of respective knockout mice. Moreover, Mrp2 (Abcc2) deficient animals display mild conjugated hyperbilirubinemia, corresponding to a human condition known as Dubin-Johnson syndrome (DJS). Naturally occurring mutations in MRP/ABCC-related drug transporters have been reported, some of which are non-synonymous single nucleotide polymorphisms. The consequences of the resulting amino acid changes can sometimes be predicted from in vitro site-directed mutagenesis studies or from knowledge of mutations of analogous (conserved) residues in ABCC proteins that cause DJS, Pseudoxanthoma elasticum (ABCC6), cystic fibrosis (CFTR/ABCC7) or persistent hyperinsulinemic hypoglycemia of infancy (SUR1/ABCC8). Continual updating of databases of sequence variants and haplotype analysis, together with in vitro biochemical validation assays and pharmacological studies in knockout animals, should make it possible to determine how genetic variation in the MRP-related transporters contributes to the range of responses to drugs and chemicals observed in different human populations.