Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:3.6.3.44 (P-glycoprotein)
13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adverse drug reactions (ADR) have increasing clinical implications and are a permanent challenge for general practitioners. Data suggest that ADR cause 3 to 18% of all hospital admissions with potentially serious consequences. Polymedication, female sex, multiple pathologies with age-related changes are predisposing factors. Antihypertensive drugs with a low bioavailability, a high protein binding capacity and specific elimination pathways are particularly prone to pharmacokinetic interactions. ACE-inhibitors, atenolol, moxonidine and diuretics have few pharmacokinetic interactions. Calcium channel blockers and beta-blockers are associated with an increased risk of pharmacokinetic drug-drug interactions. Diltiazem and verapamil are particularly prone to interactions, as they strongly inhibit the elimination of drugs undergoing the CYP3A4 and P-glycoprotein pathways.
...
PMID:[Antihypertensive therapy and drug-drug interactions]. 1623 31

A single-site modification of paclitaxel analogs at the C10 position on the baccatin III core that reduces interaction with P-glycoprotein in bovine brain microvessel endothelial cells is described. Modification and derivatization of the C10 position were carried out using a substrate controlled hydride addition to a key C9 and C10 diketone intermediate. The analogs were tested for tubulin assembly and cytotoxicity, and were shown to retain potency similar to paclitaxel. P-glycoprotein interaction was examined using a rhodamine assay and it was found that simple hydrolysis or epimerization of the C10 acetate of paclitaxel and Taxol C can reduce interaction with the P-glycoprotein transporter that may allow for increased permeation of taxanes into the brain.
...
PMID:Single-site chemical modification at C10 of the baccatin III core of paclitaxel and Taxol C reduces P-glycoprotein interactions in bovine brain microvessel endothelial cells. 1628 36

The aim of this work was to determine the expression of P-glycoprotein (P-gp) on peripheral lymphocytes (CD3) in children with steroid-dependent nephrotic syndrome (SDNS) during cyclosporine A (CyA) and ACE-inhibitor (ACE-I) treatment. The study group (I) consisted of 20 children with SDNS aged 5-18 years, with a subsequent proteinuria relapse at the time of prednisone dose reduction. All nephrotic syndrome (NS) children were examined three times: A--at proteinuria relapse, before CyA treatment; B--after 3 months; C--after 12 months of CyA administration. The control group (II) consisted of 20 healthy children. CD3/P-gp was measured using a flow cytometry assay. The serum CyA level was assessed by means of the immunofluorescence method. The expression of CD3/P-gp in NS relapse, prior to CyA+ACE-I administration, was much higher (median 9.15%, range 1.50-13.50%) when compared to healthy controls (median 1.20%, range 0.30-5.70%). The absolute number of CD3/P-gp in this examination was almost five times higher when compared to healthy controls (p<0.01). After 3 months of CyA+ACE-I therapy, the expression of CD3/P-gp decreased dramatically and was similar to the controls. Similar results were obtained after 12 months of treatment. A strong negative correlation was found between CD3/P-gp and serum CyA concentration in both examinations (r=-0.624, p<0.01; r=-0.464, p<0.01). We conclude that the results of our studies indicate that CyA+ACE-I in SDNS inhibits the expression of P-gp. CyA is an alternative therapy that may lead to the optimization of glucocorticoid (GC) doses, thus, reducing the risk that is associated with the treatment.
...
PMID:Expression of multidrug resistance P-glycoprotein on lymphocytes from nephrotic children treated with cyclosporine A and ACE-inhibitor. 1702 47

We examined the blood-brain barrier (BBB) function in methylazoxymethanol acetate (MAM)-treated rats, a model of human developmental brain malformations. We found aberrant vessels morphology and serum albumin leakage in the heterotopic (malformed) hippocampus; these changes were associated with a significant increase in endothelial P-glycoprotein (P-gp) expression. Seizures exacerbated BBB leakage and greatly augmented P-gp expression in vessels and additionally in perivascular/parenchymal astrocytes. The effects of seizures were observed to a much larger extent in malformed than in normal brain tissue. The intrinsic changes in BBB function in MAM-exposed rats were associated with increased blood-to-brain penetration of ondansetron, a P-gp substrate. However, a marked reduction in drug brain levels was provoked by seizures, and this effect was reversed by selective blockade of P-gp activity with tariquidar. Changes in BBB function may critically contribute to determine the brain uptake and distribution of P-gp substrates in epileptic tissue associated with developmental malformations.
...
PMID:Determinants of drug brain uptake in a rat model of seizure-associated malformations of cortical development. 1702 74

Silymarin consists of a family of flavonoids (silybin, isosilybin, silychristin, silydianin and taxifoline) commonly found in the dried fruit of the milk thistle plant Silybum marianum. Although silymarin's role as an antioxidant and hepatoprotective agent is well known, its role as an anticancer agent has begun to emerge. Extensive research within the last decade has shown that silymarin can suppress the proliferation of a variety of tumor cells (e.g., prostate, breast, ovary, colon, lung, bladder); this is accomplished through cell cycle arrest at the G1/S-phase, induction of cyclin-dependent kinase inhibitors (such as p15, p21 and p27), down-regulation of anti-apoptotic gene products (e.g., Bcl-2 and Bcl-xL), inhibition of cell-survival kinases (AKT, PKC and MAPK) and inhibition of inflammatory transcription factors (e.g., NF-kappaB). Silymarin can also down-regulate gene products involved in the proliferation of tumor cells (cyclin D1, EGFR, COX-2, TGF-beta, IGF-IR), invasion (MMP-9), angiogenesis (VEGF) and metastasis (adhesion molecules). The antiinflammatory effects of silymarin are mediated through suppression of NF-kappaB-regulated gene products, including COX-2, LOX, inducible iNOS, TNF and IL-1. Numerous studies have indicated that silymarin is a chemopreventive agent in vivo against a variety of carcinogens/tumor promoters, including UV light, 7,12-dimethylbenz(a)anthracene (DMBA), phorbol 12-myristate 13-acetate (PMA) and others. Silymarin has also been shown to sensitize tumors to chemotherapeutic agents through down-regulation of the MDR protein and other mechanisms. It binds to both estrogen and androgen receptors, and down-regulates PSA. In addition to its chemopreventive effects, silymarin exhibits antitumor activity against human tumors (e.g., prostate and ovary) in rodents. Various clinical trials have indicated that silymarin is bioavailable and pharmacologically safe. Studies are now in progress to demonstrate the clinical efficacy of silymarin against various cancers.
...
PMID:Anticancer potential of silymarin: from bench to bed side. 1720 Nov 69

The central objective of the current study was to investigate the potential in vitro anti-proliferative properties of the parent ligand, coumarin-dioxy-acetic acid (cdoaH(2)), and its copper complex, copper-coumarin-dioxyacetic acetate-phenathroline ([Cu(cdoa)(phen)(2)]) using four human-derived model cell lines, two neoplastic and two non-neoplastic. In addition, selected mechanistic studies were carried out using one of the neoplastic-derived model cell lines, Hep-G2. Results obtained show that the complex, rather than the ligand, could alter the proliferation of both human neoplastic renal (A-498) and hepatic (Hep-G2) cells. Furthermore, hepatic non-neoplastic cells (Chang) appeared to be less sensitive. However, this effect was not mirrored in non-neoplastic renal (HK-2) cells, a profile shared with cisplatin. The observed anti-proliferative effect appeared to be concentration- and time-dependant, and could be attributed to the complex, rather than any of the component parts, i.e. 1,10-phenanthroline, the coumarin ligand, or the simple metal salt. Furthermore, the complex was shown to decrease DNA synthesis, but did not intercalate with it. Based on IC(50) values, [Cu(cdoa)(phen)(2)] was shown to be almost six times more potent than cisplatin. Moreover, there was no evidence to show that P-glycoprotein (P-gp)-mediated multi-drug resistance (MDR) was likely to play a role in decreasing the anti-proliferative activity of the complex. Cytological stains, analysis of genomic DNA, and biochemical assays [caspase-3 and -9 and cleaved poly(ADP-ribose)-polymerase protein], suggested that cell death could switch between apoptosis and necrosis, and this effect appeared to be concentration-dependent. Additionally, flow cytometric analysis showed that the complex functioned through an alteration in cell cycle progression. Taken together, [Cu(cdoa)(phen)(2)] has been shown to be a more potent anti-proliferative agent than either the ligand or cisplatin, and is capable of altering key biochemical events leading to the execution of apoptotic and/or necrotic cell death, suggesting that it is worthy of further investigation.
...
PMID:An in vitro investigation of the induction of apoptosis and modulation of cell cycle events in human cancer cells by bisphenanthroline-coumarin-6,7-dioxacetatocopper(II) complex. 1751 8

The authors have previously shown that medroxyprogesterone acetate (MPA) inhibits growth and increases drug sensitivity in C6 glioma with myeloid bodies. Myeloid bodies can occur in cells either due to robust toxicity with mitochondrial membrane disruption or due to milder events such as seen in lysosomal-phospholipidosis. Exact patterns of myelinosis accompanying to MPA chemo-sensitization is important, because uncoupling of nuclear versus mitochondrial toxicity of anti-neoplastics by MPA would lead to safer employment of glioma chemotherapy with reduced neurotoxicity. By monitoring and comparing cell kinetics with fine structural features of cell death, the authors estimated subcellular effects accompanying growth-inhibitory drug actions in C6 glioma. The analysis revealed that MPA induced mainly lysosomal phospholipidosis, while inhibiting clonogenicity alone and augmenting procarbazine efficacy. It induced apoptosis in combination with cisplatin. It reduced mitochondrial-damage-based early cytotoxicity of methotrexate, yet it did not hinder its anti-clonogenic efficacy. Progesterone analogues - similar to antidepressants - inhibit cholesterol esterification, and this efficacy relates with their P-glycoprotein inhibition. Reducing esterification and plasma-membrane localization of cholesterol may lead MPA induction of lysosomal phospholipidosis, growth indolency, and drug sensitization in glioma.
...
PMID:Medroxyprogesterone acetate induces c6 glioma chemosensitization via antidepressant-like lysosomal phospholipidosis/myelinosis in vitro. 1772 57

Myxobacteria are gliding bacteria that belong to the delta-Proteobacteria and are known for their unique biosynthetic capabilities. Among myxobacteria, Nannocystis spp. are most closely related to marine myxobacteria and their secondary metabolism has hardly been investigated. Phenylnannolones A (1), B (2) and C (3) were obtained from a culture of Nannocystis exedens that was isolated from the intertidal region of Crete. Compound 1 had inhibitory activity toward the ABCB1 gene product P-glycoprotein and reversed daunorubicin resistance in cultured cancer cells. Phenylnannolone A has an unusual structural architecture; it is composed of an ethyl-substituted polyene chain linked to a pyrone moiety on one side and to a phenyl ring on the other. The investigation of the biosynthesis with labelled precursors revealed acetate, butyrate and phenylalanine as building blocks for 1. The labelling pattern suggested novel biochemical reactions for the biosynthesis of the starter unit.
...
PMID:Phenylnannolones A-C: biosynthesis of new secondary metabolites from the myxobacterium Nannocystis exedens. 1904 Feb 44

Glucocorticoid excess in utero inhibits fetal growth and programs adverse outcomes in adult offspring. Access of maternal glucocorticoid to the glucocorticoid receptor (NR3C1) in the placenta and fetus is regulated by metabolism via the 11beta-hydroxysteroid dehydrogenase (HSD11B) enzymes, as well as multidrug resistance P-glycoprotein (ABCB1)-mediated efflux of glucocorticoids from the syncytiotrophoblast. This study determined expression of genes encoding the two HSD11B isoforms (Hsd11b1 and Hsd11b2), the two ABCB1 isoforms (Abcb1a and Abcb1b), and Nr3c1 in the junctional and labyrinth zones of rat placentas at Days 16 and 22 of normal gestation (Day 23 is term). To assess possible regulation of the Hsd11b and Abcb1 isoforms by glucocorticoids and progesterone, their placental expression was also measured at Day 22 after partial progesterone withdrawal from Day 16 (maternal ovariectomy plus full estrogen and partial progesterone replacement) or after treatment with dexamethasone acetate (1 microg/ml of drinking water from Day 13). Expression of Hsd11b1 mRNA increased in the labyrinth zone (the site of maternal-fetal exchange) from Day 16 to Day 22, whereas that of Hsd11b2 fell dramatically. Consistent with these changes, corticosterone levels increased 10-fold in the labyrinth zone over this period. Expression of both Abcb1a and Abcb1b was markedly higher in the labyrinth zone compared with the junctional zone on both days, consistent with the proposed barrier role of ABCB1 in the placenta. Nr3c1 mRNA expression was similar in the two placental zones at Day 16 but increased 3-fold in the labyrinth zone by Day 22. Partial progesterone withdrawal increased Hsd11b1 mRNA and protein expression in the labyrinth zone but decreased Nr3c1 mRNA expression. These data show that the dynamic expression patterns of the placental HSD11Bs in late gestation are associated with dramatic shifts in placental corticosterone. Moreover, the late gestational rise in labyrinthine Hsd11b1 seems to be driven by the normal prepartum fall in progesterone level.
...
PMID:Changes in the placental glucocorticoid barrier during rat pregnancy: impact on placental corticosterone levels and regulation by progesterone. 1920 48

The use of the calcineurin inhibitors cyclosporine and tacrolimus led to major advances in the field of transplantation, with excellent short-term outcome. However, the chronic nephrotoxicity of these drugs is the Achilles' heel of current immunosuppressive regimens. In this review, the authors summarize the clinical features and histologic appearance of both acute and chronic calcineurin inhibitor nephrotoxicity in renal and nonrenal transplantation, together with the pitfalls in its diagnosis. The authors also review the available literature on the physiologic and molecular mechanisms underlying acute and chronic calcineurin inhibitor nephrotoxicity, and demonstrate that its development is related to both reversible alterations and irreversible damage to all compartments of the kidneys, including glomeruli, arterioles, and tubulo-interstitium. The main question--whether nephrotoxicity is secondary to the actions of cyclosporine and tacrolimus on the calcineurin-NFAT pathway--remains largely unanswered. The authors critically review the current evidence relating systemic blood levels of cyclosporine and tacrolimus to calcineurin inhibitor nephrotoxicity, and summarize the data suggesting that local exposure to cyclosporine or tacrolimus could be more important than systemic exposure. Finally, other local susceptibility factors for calcineurin inhibitor nephrotoxicity are reviewed, including variability in P-glycoprotein and CYP3A4/5 expression or activity, older kidney age, salt depletion, the use of nonsteroidal anti-inflammatory drugs, and genetic polymorphisms in genes like TGF-beta and ACE. Better insight into the mechanisms underlying calcineurin inhibitor nephrotoxicity might pave the way toward more targeted therapy or prevention of calcineurin inhibitor nephrotoxicity.
...
PMID:Calcineurin inhibitor nephrotoxicity. 1921 75


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---