孕烷X受体(PXR)对药物代谢途径的调控

目的 从孕烷X受体（PXR）对药物代谢途径的调控入手,在代谢性药物相互作用、PXR在CYP3A4调控中的作用及其调控机制等方面作分析和阐述。方法 结合近年来国内外相关文献进行评述。结果 PXR是CYP3A4的主要转录调控因子,药物通过PXR介导的信号通路调节CYP3A4的表达是影响药物体内代谢变化的重要途径。结论 就临床药物而言,由PXR介导的CYP3A4酶蛋白表达的改变可造成合用药物药效的减弱甚至丧失,因此必须引起广大临床药师的足够重视。     

孕烷X受体对CYP3A基因表达的调控作用及其在药物代谢中的意义

细胞色素P450 3A(cytochrom e P4503As,CYP3As)在药物代谢过程中起重要作用,外源性化学物对肝脏CYP3A基因表达有明显的诱导作用。孕烷X受体(pregnane X recep-tor,PXR)是新发现的孤儿核受体(系统名:NR1 I2)。PXR与另一重要核受体RXR结合形成二聚体结合于CYP3A基因顺式反应元件,参与对CYP3A基因表达的调控作用。大量临床处方药物通过激活PXR而诱导CYP3A基因表达,构成了临床药物间相互作用的分子基础。     

中草药对孕烷X受体和组成型雄烷受体等核受体通路影响的研究进展

孕烷X受体（pregnane X receptor,PXR）是核受体亚家族的成员之一,参与大量的外源性和内源性化学物质的生物转化,能被多种中草药激活,调节下游靶基因的表达,在药物代谢酶和转运体的调节中起重要作用。组成型雄烷受体（constitutive androstane receptor,CAR）和PXR一样能与外源性配体结合调节CYP2B6、CYP3A4、CYP2C19、UGT1A1的表达,共同参与CYP药物代谢酶的调节,成为药物作用的靶标。     

共表达PXRLBD和SRC88以及PXR配体筛选的平衡透析模型的建立

孕烷X受体(pregnane X receptor,PXR),属核受体NR1I亚家族.PXR可由配体活化,当配体(如外源药物)与其配体结合域(ligand binding domain,LBD)结合后,PXR被活化,招募辅调控因子(如人甾体受体辅活化因子-1,steroid receptor eoactivator-1,SRC-1)形成复合物,通过其DNA结合域(DNA binding domain)结合到药物代谢酶基因启动子的特定DNA序列上,从而调控CYP3A4等药物代谢酶基因的转录[1,2].     

lncRNA HNF4α-AS1参与调控转录因子和细胞色素CYP450表达

目的细胞色素P450酶系(CYP450s)是体内主要的氧化代谢酶系。临床上70%以上的处方药物经由CYP450s催化代谢。研究表明,转录因子参与CYP450s的表达调控,其中转录因子HNF4α在CYP450s的转录调控中发挥重要的作用。近期发现转录因子附近的一些非编码RNA(lnc RNA)参与其邻近基因的调节。lnc-HNF4α(HNF4α-AS1)与HNF4α相邻,是HNF4α基因的互补反义RNA。本文目的是探讨在肝癌细胞Huh7中lnc RNAHNF4α-AS1对转录因子与CYP450s表达的调控作用。方法在肝癌细胞huh7上进行功能缺失实验敲除HNF4α以及功能缺失实验敲除HNF4α-AS1与功能获得实验过表达HNF4α-AS1,q-PCR法检测lnc RNA和代谢酶以及转录因子mRNA的表达。结果在肝癌细胞Huh7中,si RNA有效干扰HNF4α后,HNF4α-AS1表达降低,CYP(1A2,2E1,2B6,2C8,2C9,2C19,3A4)的mRNA的表达以及转录因子(PXR,CAR,AhR)mRNA表达降低。在Huh7细胞中,si RNA有效干扰HNF4α-AS1后,CYP(1A2,2C8,2C9,2C19,3A4)的表达以及核受体PXR的mRNA表达升高,有效过表达HNF4α-AS1后,CYP450s以及核受体PXR的mRNA表达下降。结论 lnc RNAHNF4α-AS1参与调控转录因子与细胞色素CYP450s的表达。     

孕烷X受体在肾脏疾病中的研究进展

核受体是一类在机体内广泛分布的转录因子，在人体生理、病理过程中发挥重要作用。孕烷X受体（pregnane X receptor，PXR）为核受体家族成员之一，参与机体物质代谢，尤其在药物代谢中起关键作用。肾脏是药物代谢的主要器官之一，PXR参与肾脏药物代谢、转运等多种调节并参与多种肾脏疾病的病理生理过程。近年来多项研究关注PXR及其调控作用对肾脏及肾脏疾病的影响。本文将从PXR在肾脏与药物代谢和转运相关酶的相互作用以及PXR在肾脏疾病中的作用等方面进行综述。     

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。     

孕烷X受体和CYP3A相关性的研究进展

CYP3A是生物体内化学物代谢的关键酶 ,孕烷X受体 (PXR)是CYP3A基因表达的转录活化因子。PXR分子结构的不同导致CYP3A的种属差异。化学物通过PXR调节CYP3A的表达可能是影响化学物体内代谢的一条重要途径。研究PXR和CYP3A的相互作用对于新药设计、指导临床合理用药、预测药物相互作用、减少药物不良反应都具有重要意义。     

孕甾烷x受体在药物代谢中的作用及研究进展

孕甾烷X受体（Pregnane X receptor,PXR）为核受体超家族中NRII亚家族成员,于肝脏和肠道中广泛表达。该受体作为药物代谢的关键调控因子广泛参与药物的吸收、分布、代谢及排泄过程。本文从药物代谢角度分别对PXR参与调节的Ⅰ、Ⅱ相代谢酶及转运体进行介绍,为临床药物相互作用及针对PXR为靶点的药物研发提供参考。     

喹硫平过量时激活核受体PXR介导的药物Ⅰ相代谢酶和Ⅲ相转运体转录促进毒物消除的解毒机制

目的:考察喹硫平(quetiapine,QTP)在常规剂量与中毒剂量下对大鼠肝脏、前额叶皮质与海马中PXR信号通路及下游代谢酶CYP3A4和转运体P-gp表达的影响,并考察药物过量中毒情况下给予PXR激活剂对大鼠PXR、CYP3A4与P-gp蛋白表达的影响,从而揭示通过激活PXR信号通路促进药物脑与肝内消除的分子机制。方法:SD大鼠随机分为4组,即空白组(Control组)、常规剂量组(Normal组)、QTP中毒未干预组(Toxic组)及QTP中毒DEX干预组(Toxic+Dex组),按分组进行4d处理后,利用Western-blot技术考察不同时间点各组大鼠的肝脏、前额叶皮质与海马中PXR、CYP3 A4、P-gp的表达。结果 :腹腔注射QTP可增加脑与肝脏内PXR、CYP3A4和P-gp的蛋白表达并呈剂量依赖性;合用地塞米松(dexamethasone,DEX)可加速中毒剂量的QTP对PXR、CYP3A4和P-gp的蛋白表达的诱导作用。结论:长期使用QTP可自我诱导核受体PXR-药物代谢酶CYP3A4/转运体P-gp这一信号通路,合用核受体PXR激动剂可加速该诱导过程。激活PXR信号通路可快速有效激活解毒系统,从而可能达到快速解毒以及保护器官的目的。本实验有助于阐明药物中毒时核受体PXR对代谢酶和转运体的调控特征及分子机制,从而为开辟新的药物中毒救治途径奠定基础,为研究新型解毒药物提供新的思路。     

Pregnane X receptor- and CYP3A4-humanized mouse models and their applications

Pregnane X receptor (PXR) is a pivotal nuclear receptor modulating xenobiotic metabolism primarily through its regulation of CYP3A4, the most important enzyme involved in drug metabolism in humans. Due to the marked species differences in ligand recognition by PXR, PXR-humanized (hPXR) mice, and mice expressing human PXR and CYP3A4 (Tg3A4/hPXR) were established. hPXR and Tg3A4/hPXR mice are valuable models for investigating the role of PXR in xenobiotic metabolism and toxicity, in lipid, bile acid and steroid hormone homeostasis, and in the control of inflammation.     

Effects of intrauterine undernutrition on the expression of CYP3A23/3A1, PXR,CAR and HNF4α in neonate rats

Cytochrome P‐450 3A (CYP3A) together with its nuclear receptors plays a critical role in drug metabolism. The present study investigated the effects of undernutrition in utero on hepatic mRNA and protein expression of the enzyme CYP3A23/3A1 and nuclear receptors including pregnane X receptor (PXR; NR1I2), constitutive androstane receptor (CAR; NR1I3) and nuclear factor‐4alpha (HNF4α; HNF4A) in neonatal rats. At gestational day 2, pregnant rats were randomly divided into two groups: nourished (fed ad libitum) and undernourished (50% of nourished group). The pups delivered by nourished rats were designated as the normal‐birth‐weight group (NBW, n=15) and those delivered by undernourished rats were designated as the low‐birth‐weight group (LBW, n=15). Hepatic mRNA expression was detected by quantitative real‐time PCR and the corresponding protein expression was examined by immunohistochemistry (IHC). Compared with NBW pups, LBW pups tended to have lower mRNA expression levels of CYP3A23/3A1, PXR and CAR but higher levels of HNF4α. Only the CAR mRNA expression differences were significant (p<0.05). mRNA expression of CYP3A23/3A1 correlated with that of HNF4α in both the LBW(r=0.808, p=0.007) and NBW (r=0.452, p=0.012) groups. CYP3A23/3A1 and CAR protein expression differed between the two groups (CYP3A23/3A1, χ²=7.87, p=0.005; CAR, χ²=12.069, p=0.001). In conclusion, these findings suggest that undernutrition may influence the mRNA expression of CAR and protein expression of both CYP3A23/3A1 and CAR in neonatal rats. Since CYP3A23/3A1 and CAR are critically involved in drug metabolism, these results may have clinical implications for optimal medication in LBW children. Copyright © 2008 John Wiley & Sons, Ltd.     

Cyp3A regulation: from pharmacology to nuclear receptors.

Among the human liver cytochrome P450s (P450s), a family of microsomal hemoproteins responsible for catalyzing the oxidative metabolism of clinically used drugs and environmental chemicals, attention has been focused on CYP3A, a form that is the most abundant and is inducible by many of its substrates. From early pharmacological studies that demonstrated induction of CYP3A by glucocorticoids and, paradoxically, by antiglucocorticoids, the existence of a nonclassical glucocorticoid receptor mechanism was inferred and prompted research that culminated in the identification of a unique member of the nuclear receptor family, the pregnane X receptor (PXR; NR1I2). It has become increasingly evident that PXR as well as other nuclear receptors mediate CYP3A induction in a unique and complex manner including inducibility by structurally diverse compounds and striking interspecies differences in induction profiles. Future understanding of the role of nuclear receptors in regulating expression of CYP3A and other genes of the P450 family offers an exciting promise of further defining the physiologic function and interindividual differences of CYP3A in health and disease.