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孕烷X受体(pregnane X receptor,PXR)是核受体家族中的一员,可调控多种药物代谢酶及转运体的表达,从而影响药物在肝脏的处置过程,增加药物性肝损伤发生的风险。深入了解PXR在药物性肝损伤中的作用,可预防或减少药物性肝损伤的发生,并有助于以PXR作为潜在靶点的新型药物的研发。 相似文献
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microRNA介导低氧对药物代谢酶和转运体的调控 总被引:1,自引:0,他引:1
低氧条件下机体的循环系统、神经系统、内分泌系统等的功能发生显著改变,这些变化影响药物在体内的吸收、分布、代谢和排泄。药物代谢酶和转运体是影响药物代谢的主要因素,微小RNA (microRNA, miRNA)除调控与药物代谢相关的基因如缺氧诱导因子、炎症因子、核受体等,还可直接作用于药物代谢酶和转运体,影响药物的体内代谢。本文通过综述低氧对miRNA及药物代谢酶和转运体的调节, miRNA调控药物代谢酶和转运体及药物代谢相关基因,低氧调节药物代谢酶和转运体的相关机制等,探讨miRNA在低氧调节药物代谢酶和转运体中的作用,提出以miRNA为核心的低氧影响药物代谢的分子机制。 相似文献
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孕烷X受体(PXR,NR1I2)是生物体内药物代谢酶和转运体基因表达的主要调控因子之一.近来研究发现,PXR介导的药物代谢酶和转运体的过表达,与化疗药物多药耐药的产生密切相关.鉴于PXR在药物代谢酶和转运体调控中的重要性和PXR转录调控的多样性,有必要对其导致的多药耐药形成机制进行更深入的研究.本文综述了PXR介导的代谢酶和转运体基因表达调控机制,及其引起化疗药物多药耐药的相关研究进展,为提高化疗药物敏感性、逆转化疗药物的多药耐药提供有效的治疗策略. 相似文献
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师少军 《中国医院药学杂志》2020,40(5):579-585
肝脏是药物代谢和排泄的主要器官。肝脏药物代谢酶和膜转运体对肝细胞内药物处置及其临床疗效和毒性产生重要影响。近年来,国内外学者发现被称为"代谢-转运互作"的动力学现象,其对药物药代动力学(生物利用度)、药物相互作用具有显著影响。药物代谢酶与转运体间的功能相互作用是目前药物代谢和药代动力学研究的热点之一。本文对肝脏代谢-转运互作进行了探究,并系统阐述了这种互作对药物(特别是Ⅱ相药物代谢)的药物相互作用、药代动力学、临床疗效和毒性反应的影响。今后应进一步阐明肝脏代谢-转运互作机制,有助于研究体内药物处置及药物相互作用,为临床合理用药提供新思路和新技术。 相似文献
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核受体(NRs)是一类配体依赖性转录因子超家族,通过内源性或外源性配体物质激活调控靶基因的转录。核受体在药物代谢酶和转运体的转录调控中发挥着重要的作用。微小RNA(MicroRNA)是一类内源性的具有调控功能的非编码RNA,其对核受体表达的改变可影响药物代谢酶和转运体的表达,进而影响药效、药物不良反应和药物相互作用。本文系统地综述microRNA对几种重要核受体调控药物代谢酶和转运体的影响。 相似文献
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《中国药理学通报》2017,(10)
药物的体内过程需经一系列的生物转化和转运途径,依赖于药物代谢酶和转运体的参与。而个体对同一药物的代谢、转运能力存在差异,这一差异不能完全用药物基因组学解释。microRNA作为表观遗传修饰的一个重要方面,是对传统遗传学的强有力补充。人体内多种药物代谢酶和转运体均受到不同的microRNA调控,同一microRNA又可同时调控不同的代谢酶或(和)转运体,二者均提示microRNA极有可能实现较为广泛的宏观调控。该文分别从microRNA对药物代谢酶的调控、对药物转运体的调控以及同时调控代谢酶及转运体的microRNA三个方向综合分析,为研究药物个体差异提出一个极好的切入点,并为合理用药和个体化医疗提供理论基础。 相似文献
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药物性肝损伤是常见药源性疾病之一,其临床诊治极为困难,且易发展成急性肝功能衰竭。相关药物基因组学研究已经发现包括CYP450、UGT、GST、NAT等药物代谢酶类,ABCB1、ABCC2等药物转运体以及人类白细胞抗原的基因多态性与药物性肝损伤具相关性。本文将综述药物性肝损伤的基因多态性研究进展,以期为药物性肝损伤的临床及时诊治和科学研究提供参考。 相似文献
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Yan Guo Bingfang Hu Yang Xie Timothy R. Billiar Jason L. Sperry Min Huang 《Expert opinion on drug metabolism & toxicology》2016,12(3):245-251
Introduction: Drug metabolism and disposition are critical in maintaining the chemical and functional homeostasis of xenobiotics/drugs and endobiotics. The liver plays an essential role in drug metabolism and disposition due to its abundant expression of drug-metabolizing enzymes (DMEs) and transporters. There is growing evidence to suggest that many hepatic and systemic diseases can affect drug metabolism and disposition by regulating the expression and/or activity of DMEs and transporters in the liver.Areas covered: This review focuses on the recent progress on the regulation of DMEs by local and systemic liver injuries. Liver ischemia and reperfusion (I/R) and sepsis are used as examples of local and systemic injury, respectively. The reciprocal effect of the expression and activity of DMEs on animals’ sensitivity to local and systemic liver injuries is also discussed.Expert opinion: Local and systemic liver injuries have a major effect on the expression and activity of DMEs in the liver. Understanding the disease effect on DMEs is clinically important due to the concern of disease-drug interactions. Future studies are necessary to understand the mechanism by which liver injury regulates DMEs. Human studies are also urgently needed in order to determine whether the results in animals can be replicated in human patients. 相似文献
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Lei Xiao 《Advanced drug delivery reviews》2010,62(13):1316-1321
Nuclear receptor crosstalk represents an important mechanism to expand the functions of individual receptors. The liver X receptors (LXR, NR1H2/3), both the α and β isoforms, are nuclear receptors that can be activated by the endogenous oxysterols and other synthetic agonists. LXRs function as cholesterol sensors, which protect mammals from cholesterol overload. LXRs have been shown to regulate the expression of a battery of metabolic genes, especially those involved in lipid metabolism. LXRs have recently been suggested to play a novel role in the regulation of drug metabolism. The constitutive androstane receptor (CAR, NR1I3) is a xenobiotic receptor that regulates the expression of drug-metabolizing enzymes and transporters. Disruption of CAR alters sensitivity to toxins, increasing or decreasing it depending on the compounds. More recently, additional roles for CAR have been discovered. These include the involvement of CAR in lipid metabolism. Mechanistically, CAR forms an intricate regulatory network with other members of the nuclear receptor superfamily, foremost the LXRs, in exerting its effect on lipid metabolism. Retinoid-related orphan receptors (RORs, NR1F1/2/3) have three isoforms, α, β and γ. Recent reports have shown that loss of RORα and/or RORγ can positively or negatively influence the expression of multiple drug-metabolizing enzymes and transporters in the liver. The effects of RORs on expression of drug-metabolizing enzymes were reasoned to be, at least in part, due to the crosstalk with LXR. This review focuses on the CAR-LXR and ROR-LXR crosstalk, and the implications of this crosstalk in drug metabolism and lipid metabolism. 相似文献
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实验动物在药物研究与开发领域中发挥着不可替代的作用。药物在体内吸收、分布、代谢及排泄(ADME)过程是其药效或毒性作用产生的前提。国内外研究表明,机体参与药物体内过程各个环节的生理功能状态具有不同程度的时间节律性。肠道转运体、肝脏药物代谢酶及肾脏在药物ADME过程中发挥着重要作用。本文综述了肠道药物转运体、肝脏药物代谢酶及肾脏排泄等环节的生理节律性现象及其分子基础和调节机制。 相似文献
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Abstract: Conjugating enzymes are traditionally recognized as one of the major biological barriers to the entry of xenobiotics/drugs into systemic circulation and represent one of the main pathways for their elimination. Similar to drugs that undergo extensive phase I metabolism, drugs that undergo extensive conjugation have poor bioavailability and are more prone to metabolism-based drug interactions. Previously, enterohepatic recycling is used to explain why certain xenobiotics have half-lives that are much longer than expected from intravenous injection studies. In addition, changes in expression levels of metabolic enzymes due to chemical induction or suppression are often recognized as the source of drug interaction or toxicity of pollutants and carcinogens. These traditional approaches, whereas yielding highly valuable information, fail to recognize the fact that many conjugates (especially hydrophilic ones) cannot permeate the cell membrane.In the present review, we will focus on the coupling process that involves both conjugating enzymes and efflux transporters. We will briefly review conjugating enzymes capable of producing highly hydrophilic metabolic products. The other focus of this review is on various transporters capable of moving negatively charged hydrophilic conjugates across the cellular membrane. Evidence will support the hypothesis that efficient coupling of the conjugating enzymes and efflux transporters enables enterohepatic recycling and enteric recycling processes. Termed as a "revolving door" theory, the hypothesis focuses on the role played by efflux transporter capable of modulating the cellular excretion of hydrophilic metabolites. Coupling process in intestine, liver and kidney will be discussed with an emphasis on the intestinal coupling process, since we have just begun to understand it. Biological consequence and new insights into how coupling process can impact bioavailability of xenobiotics, biological functions of drugs and carcinogens, and drug interactions will be discussed. 相似文献
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An integrated approach to model hepatic drug clearance. 总被引:2,自引:0,他引:2
It has been well accepted that hepatic drug extraction depends on the blood flow, vascular binding, transmembrane barriers, transporters, enzymes and cosubstrate and their zonal heterogeneity. Models of hepatic drug clearances have been appraised with respect to their utility in predicting drug removal by the liver. Among these models, the "well-stirred" model is the simplest since it assumes venous equilibration, with drug emerging from the outflow being in equilibrium with drug within the liver, and the concentration is the same throughout. The "parallel tube" and dispersion models, and distributed model of Goresky and co-workers have been used to account for the observed sinusoidal concentration gradient from the inlet and outlet. Departure from these models exists to include heterogeneity in flow, enzymes, and transporters. This article utilized the physiologically based pharmacokinetic (PBPK) liver model and its extension that include heterogeneity in enzymes and transporters to illustrate how in vitro uptake and metabolic data from zonal hepatocytes on transport and enzymes may be used to predict the kinetics of removal in the intact liver; binding data were also necessary. In doing so, an integrative platform was provided to examine determinants of hepatic drug clearance. We used enalapril and digoxin as examples, and described a simple liver PBPK model that included transmembrane transport and metabolism occurring behind the membrane, and a zonal model in which the PBPK model was expanded three sets of sub-compartments that are arranged sequentially to represent zones 1, 2, and 3 along the flow path. The latter model readily accommodated the heterogeneous distribution of hepatic enzymes and transporters. Transport and metabolic data, piecewise information that served as initial estimates, allowed for the unknown efflux and other intrinsic clearances to be estimated. The simple or zonal PBPK model provides predictive views on the hepatic removal of drugs and metabolites. 相似文献
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Michael R. Boyd John J. Grygiel Rodney F. Minchin 《Clinical and experimental pharmacology & physiology》1983,10(1):87-99
Historically, the concept of metabolic activation was first forwarded to explain the in vivo activity of certain carcinogenic chemicals that without prior metabolism were chemically inert and biologically inactive. Subsequently, the concept has been extended to explain the effects of many different classes of chemicals causing diverse toxicities. Because of its major role in drug metabolism, the liver is a prominent site for toxic injury by agents requiring metabolic activation. The liver can also be the source of reactive metabolites that damage extrahepatic organs. But, organ selective toxicity can also result from the in situ metabolic activation of foreign chemicals in extrahepatic target tissues such as the lungs and the kidneys. Moreover, extrahepatic tissues generally are much more heterogeneous in cellular composition compared to the liver, and the localization of drug metabolizing enzymes in certain cell populations may result in highly cell selective toxic injury. The significance of metabolic activation and toxicity--and the importance of the particular chemical structure of individual compounds, as well as host factors such as species, age, sex, and pretreatment effects--on target-organ-selective toxicity by reactive metabolites are illustrated by studies with various furan derivatives, an important class of environmental chemicals. 相似文献
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非酒精性脂肪肝(NAFLD)是一种最常见的慢性肝病,严重威胁人类健康。在影响药物代谢的各种因素中,慢性肝病所起的作用最重要,可导致肝脏基因表达、mRNA及蛋白表达改变。非酒精性脂肪肝动物模型和非酒精性脂肪肝炎患者的研究结果显示,非酒精性脂肪肝时药物代谢酶及药物转运体发生显著改变。药物代谢酶和药物转运体在药物代谢过程中发挥重要作用,其改变可能影响药物在体内的清除,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。随着非酒精性脂肪肝的流行,越来越多的药物用于非酒精性脂肪肝患者。因此本文就非酒精性脂肪肝对药动学影响的研究进展作一综述。 相似文献