肝脏转运体和代谢酶在化学性肝损伤中的作用

肝脏是机体重要的代谢和解毒器官。肝细胞膜上存在多种功能性膜蛋白即肝脏药物转运体,它的功能是介导许多内源性及外源性物质如药物摄取进入肝脏,在肝脏内经过一定的代谢转化,最终将其从肝脏排入胆汁。研究发现,转运体和代谢酶在化学性肝损伤的发展过程中发挥重要的作用,其涉及的多种调控机制成为研究热点。就肝脏转运体和代谢酶的分类、转运体和代谢酶在化学性肝损伤中的变化及其调控机制作一综述。     

药物转运体和代谢酶在抗生素药动学中的作用

近年来,对体内药物转运体的研究取得了重大进展,越来越多的转运体被发现及研究,其对药物的跨膜转运,具有重要的意义。各种转运体包括摄取转运体和外排转运体对药物的体内过程以及药物相互作用均有着重要影响。研究表明大多数抗生素的体内过程都与转运体和代谢酶有关,因此,归纳总结了转运体和代谢酶在抗生素的药动学和药物相互作用中的最新研究进展,为临床合理用药提供参考。     

转运体和核受体影响药物代谢的研究进展

转运体是存在于体内几乎所有器官上的有转运功能的蛋白,对药物在体内的吸收、分布、代谢和排泄有非常重要的作用.而核受体是存在于细胞内的配体依赖性转录因子,可以激活配体影响代谢酶和转运体的表达和活性,进而影响药物在机体内代谢.本文综述了转运体和核受体家族中几个重要的成员以及它们对药物代谢影响的研究进展.     

微小RNA对核受体调控药物代谢酶和转运体的研究现状

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。     

代谢酶和转运体介导的草药-化学药相互作用安全性研究进展

目的 分析药物代谢酶和转运体介导的草药-化学药相互作用(herb-drug interactions,HDIs)和不良反应发生机制,总结常用草药与化学药物之间潜在相互作用的信息.方法 通过PubMed、Web of Science和中国知网等文献检索数据库,对草药、转运体、代谢酶等关键词进行文献检索.结果 草药与化学药...     

雷公藤对药物代谢酶和转运体的调控作用研究进展

目的：综述近年来雷公藤对药物代谢酶及转运体的调控进展。方法：查阅近年来国内外报道中雷公藤对药物代谢酶及转运体调控的文献,并进行归纳总结。结果：雷公藤可以抑制CYP3A4、CYP2C11等多种Ⅰ相代谢酶体外活性。而在体内实验中,大剂量的雷公藤可以强抑制CYP3A、并诱导CYP2C11和CYP2E1的表达。雷公藤对UGT1A6、UGT2B7以及GST也有抑制,但可以诱导Nrf2基因的表达。此外,雷公藤对P-gp和MDR1的基因表达存在抑制作用。结论：雷公藤对多种药物代谢酶和转运体具有抑制或诱导作用,因而雷公藤可能与其他药物发生相互作用。     

孕烷X受体在药物性肝损伤中的研究进展

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。     

中药治疗胆汁淤积性肝病作用机制的研究进展

胆汁淤积性肝病具有临床发病率高、病因复杂、发病机制不明确的特点.目前,有关胆汁淤积性肝病的有效治疗药物相对匮乏,中医药治疗胆汁淤积肝损伤(CLI)疗效及其作用机制研究备受关注.常用中药包括清热利湿类、活血化瘀类或凉血化痰类单味药及相关复方,其改善CLI的作用机制研究多聚焦在法尼醇X受体(FXR)、组成型雄甾烷受体(CA...     

姜黄素对药物代谢酶和转运体影响的研究进展

姜黄素(curcurmin,Cur)是传统药物姜黄的主要有效成分,生活中可作为调料和食物染色剂。大量研究证明姜黄素有许多重要的生物学作用,包括抗炎、抗氧化、抗癌、促进伤口愈合、防治心血管疾病和神经系统退变性疾病等[1-2],     

Proteomic analysis for the impact of hypercholesterolemia on expressions of hepatic drug transporters and metabolizing enzymes

1. Our objective is to investigate the alterations of hepatic drug transporters and metabolizing enzymes in hypercholesterolemia. Male Sprague–Dawley rats were fed high-cholesterol chows for 8 weeks to induce hypercholesterolemia. Protein levels of hepatic drug transporters and metabolizing enzymes were analyzed by iTRAQ labeling coupled with LC TRIPLE-TOF.

2. Total 239 differentially expressed proteins were identified using proteomic analysis. Among those, protein levels of hepatic drug transporters (MRP2, ABCD3, OAT2, SLC25A12, SCL38A3, SLC2A2 and SLC25A5) and metabolizing enzymes (CYP2B3, CYP2C7, CYP2C11, CYP2C13, CYP4A2 and UGT2B) were markedly reduced, but the levels of CYP2C6 and CYP2E1 were increased in hypercholesterolemia group compared to control. Decreased expressions of drug transporters MRP2 and OAT2 were further confirmed by real time quantitative PCR (RT-qPCR) and western blot.

3. Ingenuity pathway analysis revealed that these differentially expressed proteins were regulated by various signaling pathways including nuclear receptors and inflammatory cytokines. One of the nuclear receptor candidates, liver X receptor alpha (LXRα), was further validated by RT-qPCR and western blot. Additionally, LXRα agonist T0901317 rescued the reduced expressions of MRP2 and OAT2 in HepG2 cells in hypercholesterolemic serum treatment.

4. Our present results indicated that hypercholesterolemia affected the expressions of various drug transporters and metabolizing enzymes in liver via nuclear receptors pathway. Especially, decreased function of LXRα contributes to the reduced expressions of MRP2 and OAT2.     

1例头孢克洛致急性胆汁淤积型药物性肝损伤儿童患者的药学监护

1例11岁儿童患者,因服用头孢克洛4 d后出现尿黄、皮肤瘙痒入院。查肝功能异常,诊断为急性胆汁淤积型药物性肝损伤,给予保肝、退黄、降酶等对症治疗。针对患者未成年和肝损伤急性加重等特点,药学监护集中于保肝药物的合理选用、糖皮质激素个体化给药方案的制定、不良反应的监测以及药物不良相互作用的干预,同时通过用药教育提高患者用药依从性,减少潜在的用药风险。治疗4周后,患者肝功能恢复正常出院。     

Evaluation of mRNA expression of human drug-metabolizing enzymes and transporters in chimeric mouse with humanized liver

The hepatic mRNA expression of human drug-metabolizing enzymes and transporters in chimeric mise with almost-completely humanized liver (replacement index: 71–89%) was investigated. The mRNAs of 58 human phase I enzymes, 26 human phase II enzymes, 23 human transporters, and five mouse Cyps were measured in the chimeric mice with humanized liver generated using hepatocytes from a Japanese donor. The mRNA expression of 52 human phase I enzymes, which includes 20 human CYPs, 26 human phase II enzymes and 21 human transporters was ascertained in the chimeric mouse liver. Among them, the expression of the target mRNAs vital for liver function such as the metabolism and secretion of endogenous compounds appeared to be maintained. The central value for the expression ratio in all target genes in chimeric mouse liver to the donor liver was 0.46, which was lower than the substitution rate of chimeric mouse liver by donor liver. The ratio of mouse Cyp mRNA expression of chimeric mouse liver to that of control mouse liver was 0.19 or less, except for that of Cyp2b10. There were good correlations between the mRNA expression levels of human hepatic albumin gene, the values of the rate of replacement of mouse liver by human liver, and the human blood albumin concentration in the chimeric mice. The chimeric mice with humanized liver may be a useful tool for the evaluation of drug–drug interactions such as the inhibition and induction of drug-metabolizing enzymes and transporters.     

Targeting the pregnane X receptor in liver injury

Introduction: The nuclear receptor pregnane X receptor (PXR) is a well-characterized hepatic xenobiotic sensor whose activation by chemically diverse compounds results in the induction of drug clearance pathways that rid the body of potentially toxic substances, thus conferring protection from foreign chemicals and endobiotics.

Areas covered: PXR activities are implicated in drug–drug interactions and endocrine disruption. Recent evidence supports a hepatoprotective role for PXR in chronic liver injury, inhibiting liver inflammation through suppression of the NF-κB pathway. However, PXR-mediated induction of CYP3A enhances APAP-induced acute liver injury by generating toxic metabolites. While these observations implicate PXR as a therapeutic target for liver injury, they also caution against PXR activation by pharmaceutical drugs.

Expert opinion: While evidence of PXR involvement in acute and chronic liver injuries identifies it as a possible therapeutic target, it raises additional concerns for all drug candidates. The in vitro and in vivo tests for human PXR activation should be incorporated into the FDA regulations for therapeutic drug approval to identify potential liver toxicities. In addition, PXR pharmacogenetic studies will facilitate the prediction of patient-specific drug reactivities and associated liver disorders.     

Expression of clinically relevant drug‐metabolizing enzymes along the human intestine and their correlation to drug transporters and nuclear receptors: An intra‐subject analysis

The oral bioavailability of many drugs is highly influenced not only by hepatic but also by intestinal biotransformation. To estimate the impact of intestinal phase I and II metabolism on oral drug absorption, knowledge on the expression levels of the respective enzymes is an essential prerequisite. In addition, the potential interplay of metabolism and transport contributes to drug disposition. Both mechanisms may be subjected to coordinative regulation by nuclear receptors, leading to unwanted drug‐drug interactions due to induction of intestinal metabolism and transport. Thus, it was the aim of this study to comprehensively analyse the regional expression of clinically relevant phase I and II enzymes along the entire human intestine and to correlate these data to expression data of drug transporters and nuclear receptors of pharmacokinetic relevance. Gene expression of 11 drug‐metabolizing enzymes (CYP2B6, 2C8, 2C9, 2C19, 2D6, 3A4, 3A5, SULT1A, UGT1A, UGT2B7, UGT2B15) was studied in duodenum, jejunum, ileum and colon from six organ donors by real‐time RT‐PCR. Enzyme expression was correlated with expression data of the nuclear receptors PXR, CAR and FXR as well as drug transporters observed in the same cohort. Intestinal expression of all studied metabolizing enzymes was significantly higher in the small intestine compared to colonic tissue. CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4/5, SULT1A, UGT1A and UGT2B7 expression increased from the duodenum to jejunum but was markedly lower in the ileum. In the small intestine, that is, the predominant site of drug absorption, the highest expression has been observed for CYP3A4, CYP2C9, SULT1A and UGT1A. In addition, significant correlations were found between several enzymes and PXR as well as ABC transporters in the small intestine. In conclusion, the observed substantial site‐dependent intestinal expression of several enzymes may explain regional differences in intestinal drug absorption. The detected correlations between intestinal enzymes, transporters and nuclear receptors provide indirect evidence for their coordinative expression, regulation and function in the human small intestine.     

大黄酸对药物转运体和代谢酶影响的研究进展

药物转运体和药物代谢酶是影响药物体内处置过程中至关重要的因素。大黄酸作为传统中药大黄的主要活性成分,具有广泛药理活性。研究发现,大黄酸与药物转运体和代谢酶密切相关,能够直接激活或抑制多种转运体的功能及其蛋白表达。而且大黄酸对药物代谢酶细胞色素P450（CYP450）的功能及其蛋白表达同样有抑制作用。因此,大黄酸与其他药物合用时,可能发生基于药动学的药物相互作用（drug-drug interaction,DDI）。从药物转运体和代谢酶的体内分布、大黄酸对转运体及代谢酶的影响等方面进行综述。     

肝脏转运蛋白在药物肝胆转运中的作用

目的对肝脏转运蛋白在药物肝胆转运中的作用作一综述,为药物肝靶向提供依据。方法根据文献,从药物不良反应、药物的矢量转运、药物肝靶向性、药物之间相互作用4个方面阐述肝脏转运蛋白对药物肝胆排泄产生的影响。结果肝脏转运蛋白引起的药物矢量转运影响药物的肝脏摄取,药物肝靶向性影响药物的疗效,药物之间相互作用影响临床用药安全和不良反应。结论肝脏转运蛋白在药物肝胆转运中起到了重要的作用,它与药物在体内各组织分布、临床疗效均有密切的联系。     

Farnesoid X receptor contributes to oleanolic acid-induced cholestatic liver injury in mice

Farnesoid X receptor (FXR) is a nuclear receptor involved in the metabolism of bile acid. However, the molecular signaling of FXR in bile acid homeostasis in cholestatic drug-induced liver injury remains unclear. Oleanolic acid (OA), a natural triterpenoid, has been reported to produce evident cholestatic liver injury in mice after a long-term use. The present study aimed to investigate the role of FXR in OA-induced cholestatic liver injury in mice using C57BL/6J (WT) mice and FXR knockout (FXR^−/−) mice. The results showed that a significant alleviation in OA-induced cholestatic liver injury was observed in FXR^−/− mice as evidenced by decreases in serum alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase as well as reduced hepatocyte necrosis. UPLC-MS analysis of bile acids revealed that the contents of bile acids decreased significantly in liver and serum, while increased in the bile in FXR^−/− mice compared with in WT mice. In addition, the mRNA expressions of hepatic transporter Bsep, bile acid synthesis enzymes Bacs and Baat, and bile acids detoxifying enzymes Cyp3a11, Cyp2b10, Ephx1, Ugt1a1, and Ugt2b5 were increased in liver tissues of FXR^−/− mice treated with OA. Furthermore, the expression of membrane protein BSEP was significantly higher in livers of FXR^−/− mice compared with WT mice treated with OA. These results demonstrate that knockout of FXR may alleviate OA-induced cholestatic liver injury in mice by decreasing accumulation of bile acids both in the liver and serum, increasing the export of bile acids via the bile, and by upregulation of bile acids detoxification enzymes.