共查询到20条相似文献,搜索用时 15 毫秒
1.
2.
David E. Amacher 《Expert opinion on drug metabolism & toxicology》2016,12(12):1463-1477
Introduction: If a drug is found to be an inducer of hepatic drug metabolizing enzymes via activation of nuclear receptors such as pregnane X receptor (PXR) or constitutive androstane receptor (CAR), it is likely that drug transporters regulated through these same receptors will be induced as well. This review highlights what is currently known about the molecular mechanisms that regulate transporter expression and where the research is directed.Areas covered: This review is focused on publications that describe the role of activated hepatic nuclear receptors in the subsequent regulation of drug uptake and/or efflux transporters following exposure to xenobiotics.Expert opinion: Many of the published studies on the role of nuclear receptors in the regulation of drug transporters involve non-human test animals. But due to species response differences, these associations are not always applicable to humans. For this reason, some relevant human in vitro models have been developed, such as primary or cryopreserved human hepatocytes, human liver slices, or HepG2 or HuH7 cell lines transiently or stably transfected with PXR expression and reporter constructs as well as in vivo models such as PXR-humanized mice. These human-relevant test systems will continue to be developed and applied for the testing of investigational drugs. 相似文献
3.
Jeff L Staudinger Ajay Madan Kathleen M Carol Andrew Parkinson 《Drug metabolism and disposition》2003,31(5):523-527
Pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are key regulators of xenobiotic-inducible cytochrome P450 gene expression. Whereas much is known about their role in regulating drug metabolism, little is known regarding their role in regulating drug transport in vivo. Wild-type mice and mice lacking PXR (PXR-KO) were used to examine the inducible expression of two drug transporter genes, Oatp2 (Slc21a5) and Mrp3 (Abcc3), in liver following treatment with selective PXR and CAR activators. Selective activation of PXR or CAR induced Oatp2 and Mrp3 expression in wild-type mice but not in PXR-KO mice. Basal expression levels of Oatp2 and Mrp3 gene were significantly higher in PXR-KO mice when compared with wild-type mice. Additionally, phenobarbital (PB)-inducible Oatp2 and Mrp3 gene expression was significantly increased in the PXR-KO mice when compared with wild-type PB-treated mice. We also examined the effect of PXR ablation on PB-inducible hepatic CYP3A activity in vivo. Microsomes isolated from PB-treated PXR-KO mice exhibited a significantly elevated rate of testosterone 6 beta-hydroxylation when compared with microsomes isolated from wild-type PB-treated mice. PB treatment produced significantly increased levels of hepatomegaly in PXR-KO mice when compared with wild-type PB-treated mice. Taken together, these results suggest that nonliganded PXR plays a net negative role in coregulating shared PXR/CAR-target gene expression in vivo and extend the hypothesis that PXR and CAR coregulate not only drug metabolism but also drug transport. 相似文献
4.
5.
6.
Peattie RA 《Current pharmaceutical biotechnology》2012,13(7):1299-1305
Hyaluronan (HA) is a highly biocompatible biopolymer that is widely used for a variety of therapeutic purposes including surgical preparations, adhesion prevention, viscosupplementation and drug and cytokine delivery. Delivery can be accomplished effectively when HA-based carriers are synthesized in the form of hydrogels, though doing so normally requires chemical modification of the native HA structure. Solute delivery from HA-based gels can be either "simple", that is from a gel not including separate components intended to control release, or "regulated" when specific components are included for that purpose. A variety of modified forms of HA have been developed and used for delivery of desired molecules in therapeutic, clinical, veterinary and laboratory research environments, and the number of such applications is likely to grow in future years. 相似文献
7.
8.
Rapid regulation of dopamine transporter function by substrates, blockers and presynaptic receptor ligands 总被引:18,自引:0,他引:18
The extracellular actions of dopamine are terminated primarily through its binding to dopamine transporters and translocation back into dopamine neurons. The transporter thereby serves as an optimal target to regulate dopamine neurotransmission. Although acute pharmacological blockade of dopamine transporters is known to reversibly inhibit transporter function by preventing the binding of its endogenous substrate dopamine, it recently has become clear that dopamine transporter substrates, such as amphetamines, and blockers, such as cocaine, also have the ability to rapidly and persistently regulate transporter function after their direct pharmacological effect has subsided. Presynaptic receptor ligands can also regulate dopamine transporter function. This has been investigated most extensively for dopamine D2 receptors, but there is also evidence for regulation by gamma-aminobutyric acid (GABA) GABAB receptors, metabotropic glutamate, nicotinic acetylcholine, serotonin, sigma2- and kappa-opioid receptors. The focus of this review is the rapid, typically reversible, regulation of dopamine transporter velocity by substrates, blockers and presynaptic receptor ligands. The research discussed here suggests that a common mechanism through which these different classes of compounds regulate transporter activity is by altering the cell surface expression of dopamine transporters. 相似文献
9.
The cytokine oncostatin M (OSM) is a member of the interleukin (IL)-6 family, known to down-regulate expression of drug metabolizing cytochromes P-450 in human hepatocytes. The present study was designed to determine whether OSM may also impair expression of sinusoidal and canalicular drug transporters, which constitute important determinants of drug hepatic clearance. Exposure of primary human hepatocytes to OSM down-regulated mRNA levels of major sinusoidal solute carrier (SLC) influx transporters, including sodium-taurocholate co-transporting polypeptide (NTCP), organic anion transporting polypeptide (OATP) 1B1, OATP1B3, OATP2B1, organic cation transporter 1 and organic anion transporter 2. OSM also repressed mRNA expressions of ATP binding cassette (ABC) efflux transporters such as multidrug resistance protein (MRP) 2/ABCC2 and breast cancer resistance protein/ABCG2, without however impairing those of multidrug resistance gene 1/P-glycoprotein/ABCB1, MRP3/ABCC3, MRP4/ABCC4 and bile salt export pump/ABCB11. The cytokine concomitantly reduced NTCP, OATP1B1, OATP2B1 and ABCG2 protein expression and NTCP and OATP transport activities. OSM effects towards transporters were found to be dose-dependent and highly correlated with those of IL-6, but not with those of other inflammatory cytokines such as tumor necrosis factor-α or interferon-γ. In addition, OSM-mediated repression of some transporters such as NTCP, OATP1B1 and OATP2B1, was counteracted by knocking-down expression of the type II OSM receptor subunits through siRNA transfection. This OSM-mediated down-regulation of drug SLC transporters and ABCG2 in human hepatocytes may contribute to alterations of pharmacokinetics in patients suffering from diseases associated with increased production of OSM. 相似文献
10.
目的 研究双胎选择性宫内生长受限(selective intrauterine growth restriction,sIUGR)胎盘血管内皮生长因子(VEGF)的表达并探讨影响妊娠结局的危险因素.方法 2010年6月至2013年6月深圳市人民医院产科分娩双胎妊娠590例,单绒毛膜双羊膜囊(monochorionic diamnotic,MCDA)双胎sIUGR 42例作为病例组,双绒毛膜双胎sIUGR 47例作为对照A组,同期分娩的无sIUGR单绒毛膜双羊膜囊双胎42例作为对照B组.分娩后收集胎盘并分别称重、检测胎盘份额、脐带插入情况.记录新生儿出生体重及围产儿结局.运用免疫组织化学法分别检测病例组和对照组胎盘组织中VEGF的表达,半定量测其表达强度.体重轻者称小胎,体重重者称大胎.结果 病例组、对照A组及对照B组围产儿死亡率分别为17.8% (15/84)、6.4%(6/94)、1.2%(1/84),脐带异常插入率分别为48.8%、10.6%、14.3%.病例组大、小胎胎盘重量为(521±149)g vs.(258±53)g.VEGF在病例组、对照A组大婴胎盘组织中的表达强度高于小婴(P<0.01).结论 单绒毛膜双羊膜囊双胎sIUGR围产儿死亡率明显升高.双胎sIUGR危险因素主要有胎盘份额分配不均衡、脐带帆状插入、胎盘血管内皮生长因子表达下降等. 相似文献
11.
Differential regulation of cadherin expression by osteotropic hormones and growth factors in vitro in human osteoprogenitor cells 总被引:1,自引:0,他引:1
Aim: To examine if cadherins are expressed constitutively in human bone marrow stromal cells (hBMSC) and investigate the regulation of cadherin expression by various osteotropic hormones and local factors. Methods: Cadherin expression was examined in first passaged (secondary) hBMSC as well as in the conditionallyimmortalized human osteoprogenitor cell line (hOP-7). Using a monoclonal antibody (MoAb C-1821) to a cytoplasmic domain common to all known cadherins (pan-cadherin MoAb), cadherins were immunolocalized in first passaged hBMSC as well as in hOP-7 cells. In addition, intense immunostaining for cadhedn expression was associated with alkaline phosphatase (ALP) in nodules formed in the high density cultures of hOP-7 cells. Human E-cadherin (HECD) was specifically detected by Western blotting in extracts of untreated hBMSC using an anti-HECD MoAb 004FD. Results: Differential regulation of cadherin expression by various osteotropic hormones and local factors (parathyroid hormone, dexamethasone,estradiol, prostaglandin E2, basic fibroblast growth factor, and tumor necrosis factor-β) was also observed. In addition, blocking cadherins with the MoAb C-1821 increased basal ALP activity and had an additive effect on 1, 25(OH)ED3-induced ALP activity. Conclusion: Cadherins are expressed in human osteoprogenitor cells and are involved in the osteogenic differentiation. The differential modulation of cadherin expression by osteotropic agents indicates that these agents may regulate osteoprogenitor cells through different cadherins and these cadherins may play different roles. 相似文献
12.
Ioannidou E 《Current pharmaceutical design》2006,12(19):2397-2408
Regeneration that takes place in the human body is limited throughout life. Therefore, when organs are irreparably damaged, they are usually replaced with an artificial device or donor organ. The term "regenerative medicine" covers the restoration or replacement of cells, tissues, and organs. Stem cells play a major role in regenerative medicine by providing the way to repopulate organs damaged by disease. Stem cells have the ability to self renew and to regenerate cells of diverse lineages within the tissue in which they reside. Stem cells could originate from embryos or adult tissues. Growth factors are proteins that may act locally or systemically to affect the growth of cells in several ways. Various cell activities, including division, are influenced by growth factors. Cytokines are a family of low-molecular-weight proteins that are produced by numerous cell types and are responsible for regulating the immune response, inflammation, tissue remodeling and cellular differentiation. Target cells of growth factors and cytokines are mesenchymal, epithelial and endothelial cells. These molecules frequently have overlapping activities and can act in an autocrine or paracrine fashion. A complex network of growth factors and cytokines guides cellular differentiation and regeneration in all organs and tissues. The aim of this paper is to review the role of growth factors and cytokines in different organs or systems and explore their therapeutic application in regenerative medicine. The role of stem cells combined with growth factors and cytokines in the regeneration of vascular and hematopoietic, neural, skeletal, pancreatic, periodontal, and mucosal tissue is reviewed. There is evidence that supports the use of growth factors and cytokines in the treatment of neurological diseases, diabetes, cardiovascular disease, periodontal disease, cancer and its complication, oral mucositis. After solving the ethical issues and establishing clear and reasonable regulations, regenerative medicine through stem cell application combined with specific growth factors and cytokines will have great potential in curing a variety of human diseases. 相似文献
13.
14.
15.
目的探讨子痫前期病人血清中白细胞介素 12(IL-12)白细胞介素 4(IL-4)及胎盘生长因子( PLGF)水平与子痫前期发病的关系。方法选择 2019年 1—5月在徐州医科大学附属医院,产科收治并分娩的子痫前期孕妇 70例,其中早发型子痫前期组 33例,晚发型子痫前期组 37例,同期住院分娩的正常妊娠孕妇 30例为对照组。采用酶联免疫吸附试验( ELISA)测定各组孕妇血清中 IL-12,IL-4,PLGF含量。采用 xˉ± s、单因素方差分析等进行统计学分析。结果早发型子痫前期组血清 PLGF含量(270.34±37.69)pg/mL低于晚发型子痫前期组( 305.32±37.77)pg/mL,两组均低于对照组( 365.76±18.94)pg/mL(P<0.05);早发型子痫前期组血清 IL-12含量( 179.36±12.93)pg/mL高于晚发型子痫前期组( 158.11±20.55)pg/mL,两组均高于对照组( 131.51±8.88)pg/mL(P<0.05);早发型子痫前期组及晚发型子痫前期组 IL-4含量( 28.82±3.76)pg/mL及( 31.36±4.01)pg/mL均低于对照组( 35.36±3.52)pg/mL(P<0.05)早发组与晚发组差异无统计学意义( P>0.05)。结论孕妇血清中 PLGF及 IL-4随着子痫前期病情进展降低, IL-12随着子期病情进展升高,提示免疫失衡可能影响胎盘功能,加剧子痫前期的病情进展。痫前, 相似文献
16.
S.-F. Zhou 《Xenobiotica; the fate of foreign compounds in biological systems》2013,43(7-8):802-832
1. P-glycoprotein (P-gp/MDR1), one of the most clinically important transmembrane transporters in humans, is encoded by the ABCB1/MDR1 gene. Recent insights into the structural features of P-gp/MDR1 enable a re-evaluation of the biochemical evidence on the binding and transport of drugs by P-gp/MDR1.2. P-gp/MDR1 is found in various human tissues in addition to being expressed in tumours cells. It is located on the apical surface of intestinal epithelial cells, bile canaliculi, renal tubular cells, and placenta and the luminal surface of capillary endothelial cells in the brain and testes.3. P-gp/MDR1 confers a multi-drug resistance (MDR) phenotype to cancer cells that have developed resistance to chemotherapy drugs. P-gp/MDR1 activity is also of great clinical importance in non-cancer-related drug therapy due to its wide-ranging effects on the absorption and excretion of a variety of drugs.4. P-gp/MDR1 excretes xenobiotics such as cytotoxic compounds into the gastrointestinal tract, bile and urine. It also participates in the function of the blood–brain barrier.5. One of the most interesting characteristics of P-gp/MDR1 is that its many substrates vary greatly in their structure and functionality, ranging from small molecules such as organic cations, carbohydrates, amino acids and some antibiotics to macromolecules such as polysaccharides and proteins.6. Quite a number of single nucleotide polymorphisms have been found for the MDR1 gene. These single nucleotide polymorphisms are associated with altered oral bioavailability of P-gp/MDR1 substrates, drug resistance, and a susceptibility to some human diseases.7. Altered P-gp/MDR1 activity due to induction and/or inhibition can cause drug–drug interactions with altered drug pharmacokinetics and response.8. Further studies are warranted to explore the physiological function and pharmacological role of P-gp/MDR1. 相似文献
17.
Cellular localization of hepatic cytochrome 1B1 expression and its regulation by aromatic hydrocarbons and inflammatory cytokines. 总被引:5,自引:0,他引:5
F Piscaglia T Knittel D Kobold S Barnikol-Watanabe P Di Rocco G Ramadori 《Biochemical pharmacology》1999,58(1):157-165
Cytochrome P450 1B1 (CYP1B1) is an activator of several xenobiotics and is induced in the liver upon experimental exposure to aromatic hydrocarbons. Since its cellular localization and regulation are incompletely clarified, Cyp1B1 expression and inducibility by 9,10-dimethyl-1,2-benzanthracene (DMBA) and inflammatory cytokines were investigated in different rat liver cell populations in vitro and in the liver during hepatocellular injury. Expression of Cyp1B1 was studied by Northern blot analysis in hepatic stellate cells (HSCs), myofibroblasts (MFs), Kupffer cells (KCs), and hepatocytes at various time points of primary cultures and in acutely damaged rat liver (carbon tetrachloride model). Enzyme inducibility was assessed by incubation of cells with DMBA as well as, in the case of HSCs, with tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor beta1 (TGFbeta1). Cyp1B1 messengers were expressed at high levels by HSCs and MFs, whereas constitutive expression was not detectable in KCs or in hepatocytes. Cyp1B1-specific mRNA were expressed at highest levels in HSCs at an early stage of activation (2 days after plating) and were diminished upon further activation. DMBA strongly enhanced Cyp1B1 gene expression in HSCs, MFs, and in hepatocytes at day 3 of primary cultures, but not in hepatocytes at day 1, or in KCs. The inflammatory cytokine TNF-alpha enhanced the Cyp1B1 gene expression in HSCs, either when administered alone or in addition to DMBA, while TGFbeta1 did not affect Cyp1B1 expression, even after DMBA induction. We conclude that HSCs and MFs seem to be the major cellular sources of hepatic Cyp1B1 expression and that the constitutive expression of the Cyp1B1 gene and the responsiveness to DMBA stimulation differ between mesenchymal and parenchymal liver cells, indicating a cell-specific regulation of Cyp1B1 gene expression. Interestingly, TNF-alpha is a potent stimulator of the Cyp1B1 gene in HSCs and acts in concert with DMBA. 相似文献
18.
Structure, function and regulation of P-glycoprotein and its clinical relevance in drug disposition 总被引:1,自引:0,他引:1
Zhou SF 《Xenobiotica; the fate of foreign compounds in biological systems》2008,38(7-8):802-832
1. P-glycoprotein (P-gp/MDR1), one of the most clinically important transmembrane transporters in humans, is encoded by the ABCB1/MDR1 gene. Recent insights into the structural features of P-gp/MDR1 enable a re-evaluation of the biochemical evidence on the binding and transport of drugs by P-gp/MDR1. 2. P-gp/MDR1 is found in various human tissues in addition to being expressed in tumours cells. It is located on the apical surface of intestinal epithelial cells, bile canaliculi, renal tubular cells, and placenta and the luminal surface of capillary endothelial cells in the brain and testes. 3. P-gp/MDR1 confers a multi-drug resistance (MDR) phenotype to cancer cells that have developed resistance to chemotherapy drugs. P-gp/MDR1 activity is also of great clinical importance in non-cancer-related drug therapy due to its wide-ranging effects on the absorption and excretion of a variety of drugs. 4. P-gp/MDR1 excretes xenobiotics such as cytotoxic compounds into the gastrointestinal tract, bile and urine. It also participates in the function of the blood-brain barrier. 5. One of the most interesting characteristics of P-gp/MDR1 is that its many substrates vary greatly in their structure and functionality, ranging from small molecules such as organic cations, carbohydrates, amino acids and some antibiotics to macromolecules such as polysaccharides and proteins. 6. Quite a number of single nucleotide polymorphisms have been found for the MDR1 gene. These single nucleotide polymorphisms are associated with altered oral bioavailability of P-gp/MDR1 substrates, drug resistance, and a susceptibility to some human diseases. 7. Altered P-gp/MDR1 activity due to induction and/or inhibition can cause drug-drug interactions with altered drug pharmacokinetics and response. 8. Further studies are warranted to explore the physiological function and pharmacological role of P-gp/MDR1. 相似文献
19.
The effect of chlorpyrifos (CPF) and its metabolite, chlorpyrifos-oxon (CPO), on multidrug resistance-1 (MDR1) gene expression and efflux transporter function in Caco-2 cells was determined. The effect of CPF and CPO on gene expression in Caco-2 cells was tested as a function of time using RT-PCR and competitive PCR (compPCR) techniques. The RT-PCR results depicted a maximal effect of CPF exposure on MDR1 expression at 8 h, which decreased at 24 h. Studies with CPO displayed an initial increase in expression at 4 h only. The compPCR assays were conducted with the CPF-treated group to quantify the changes in gene expression levels. The compPCR data confirmed and quantitated the results from the time-course study using semiquantitative RT-PCR. In addition to the gene expression studies, changes in efflux transporter function were investigated using Caco-2 cells grown on semipermeable membranes in Transwell plates. The permeability of verapamil was determined in cells treated for 8 h with CPF. Efflux ratios demonstrated that verapamil was effluxed at a higher rate from the CPF-treated cells as compared to the control group, confirming the inductive action of CPF on transporter function. These results suggest that CPF has the potential to modulate the bioavailability of drugs via changes in expression and function of membrane efflux transporters. 相似文献
20.
YoshT 《中国药理学与毒理学杂志》2002,16(6):407-408
It has been well known that inflammation leads to the decreased ability of drug metabolism in human and animals.Since many inflammatory and anti-inflammatory cytokines produced under the inflammatory conditions,their possible roles in the regulation of drug metabolizing enzymes,specifically cytochrome P450s(CYPs),have been examined to date.Lipopolysaccharide (LPS) produces many cryokines and decreases drug medabolism.LPS is also a potent inducer of heme oxygenase(HO-1).We found that LPS produced the induction of HO-1 via TNFα rather than IL-1,be employing each cytokine knockout mice.Additionally,arthritis model mice exhibited the increase in HO-1 without any changes in total CYP content.Effects of chemicals on HO-1 and CYPs in cytokine knockout mice will also be discussed. 相似文献