Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We established previously that lipopolysaccharide (LPS) can induce the expression of LPS-binding sites on bone marrow cells (BMC). We now report that staurosporine (STP), a glycosylated indolocarbazole alkaloid with potent inhibitory activity for various protein kinases, can induce the same effect. With both agents, the newly expressed LPS receptor was found to be CD14. The STP-induced effect was independent of its protein kinase inhibitory activity because several other protein kinase inhibitors, such as the indolocarbazole K-252a, the bisindolylmaleimide RO-31-8220, the perylenequinone calphostin C, and the isoquinolinesulfonamide H7, did not induce CD14 expression. The observation that the STP analog K-252a with an identical polyaromatic aglycon moiety was inactive yet the analog UCN-01 with an identical glycoside ring was active suggests that the induction of CD14 expression is triggered by the sugar moiety of STP. Three lines of evidence show that the mechanism of CD14 expression induced by STP differs from that induced by LPS: (i) unlike LPS, STP can stimulate BMC from LPS-unresponsive C3H/HeJ mice, (ii) LPS and STP effects are additive at a saturating dose of LPS, and (iii) the protein kinase inhibitor K-252a inhibits the LPS-induced but not STP-induced stimulation. Therefore, our findings show that both a protein kinase-dependent (LPS-induced) and a protein kinase-independent (STP-induced) mechanism can lead to the expression of the LPS receptor CD14 on BMC. We also found that the STP-induced stimulation of BMC is modulated by cyclosporin A, vinblastine, and verapamil. This observation may suggest that the inducible effect of STP could be initiated by its interaction with P-glycoprotein, a membrane pump with drug efflux function that plays a critical role in the multidrug resistance of cancer cells.
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PMID:Lipopolysaccharide and the glycoside ring of staurosporine induce CD14 expression on bone marrow granulocytes by different mechanisms. 938 33

P-glycoprotein (PGP), an ATP-dependent membrane transporter is found in epithelial tissues of the liver, kidneys, intestine and blood-brain barrier. In tumor cells, PGP is often overexpressed and confers multidrug resistance toward cancer chemotherapeutics. It has been previously shown in rats that induction of an inflammatory response evokes a decrease in hepatic expression of PGP. In order to identify the inflammatory mediators involved in this phenomenon, we examined the influence of experimentally induced inflammation and pro-inflammatory cytokines (interleukin (IL)-6, IL-1beta and tumor necrosis factor (TNF)-alpha) on the hepatic expression of PGP in mice. A significant reduction in the hepatic expression of mdr1a, mdr1b, mdr2 and spgp genes were seen in endotoxin (lipopolysaccharide (LPS)) and turpentine-treated mice. Similarly, IL-6-treated mice displayed a 70% reduction in protein expression and a 40-70% reduction in the mRNA levels of all PGP mdr isoforms. Administration IL-1beta caused an increase in both mdr1b mRNA and protein expression, however, mRNA levels of mdr1a, mdr2 and spgp were significantly reduced. Administration of TNF-alpha also caused increases in mdr1b mRNA. These findings indicate that IL-6 plays a principal role in the downregulation of PGP that is observed in the livers of mice during an inflammatory response.
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PMID:Regulation of the hepatic multidrug resistance gene expression by endotoxin and inflammatory cytokines in mice. 1136 Sep 20

The multidrug resistance gene product, P-glycoprotein, may act as a defense mechanism against natural and man-made environmental toxins. Like mammals, chickens show high levels of P-glycoprotein expression in the liver, small intestine, and kidney. Expression of P-glycoprotein rapidly increased with age in the liver and kidney reaching a plateau by 2 and 4 days of age, respectively; however, expression of P-glycoprotein in the duodenum did not significantly change with age. Addition of dietary antibiotics (monensin, bacitracin), as models for dietary toxins, altered P-glycoprotein expression. Monensin increased P-glycoprotein expression in the liver and duodenum. Bacitracin reduced P-glycoprotein expression by 45% in the liver, but did not alter expression in the duodenum. Intraperitoneal injection of E. coli lipopolysaccharide, a model for acute inflammation, rapidly increased expression of Pgp protein in the liver ( approximately 2-fold). Expression then declines to pre-induction levels by 24 h. Similar responses were observed in the spleen and kidney but not the duodenum. These results confirm the presence of an avian P-glycoprotein homologue and suggest that dietary constituents regulate the expression of P-glycoprotein. Changes in P-glycoprotein expression may represent an important physiological response to foods containing toxins and an important component of the acute phase immune response.
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PMID:Expression of P-glycoprotein in the chicken. 1154 75

Lipopolysaccharide-induced changes in blood-brain barrier (BBB) permeability were investigated with a pharmacological approach in vitro. Lipopolysaccharide induced a concentration- and time-dependent (non)reversible opening of the BBB, and brain astrocytes make brain capillary endothelial cells (BCEC) resistant to this BBB disruption. De novo protein synthesis was essential for the recovery, because cycloheximide prevented the recovery process. Dexamethasone pretreated BCEC were more resistant to lipopolysaccharide, while no protective response was induced by heat shock nor by inhibition of P-glycoprotein. BBB opening was tempered by free radical inhibitors (i.e., pretreatment with N-acetyl-cysteine or uric acid combined with deferroxamine mesylate). No effects of modulators of prostanoid-, leukotriene-, or platelet-activating factor pathways were observed. Therefore, lipopolysaccharide-induced BBB opening seems to be primarily mediated by excessive free radical production.
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PMID:Pharmacological investigations on lipopolysaccharide-induced permeability changes in the blood-brain barrier in vitro. 1253 68

1. Inflammation is a pathophysiological event that has relevance for altered drug disposition in humans. Two functions of P-glycoprotein (P-gp) are hepatic drug elimination and prevention of drug entry into the central nervous system (CNS). Our objective was to investigate if localized CNS inflammation induced by Escherichia coli lipopolysaccharide (LPS) would modify mdr1a/P-gp expression and function in the brain and liver. 2. Our major finding was that the CNS inflammation in male rats produced a loss in the expression of mdr1a mRNA in the brain and liver that was maximal 6 h after intracranial ventricle (i.c.v.) administration of LPS. When (3)H-digoxin was used at discrete time points, as a probe for P-gp function in vivo, an increase in brain and liver (3)H-radioactivity and plasma level of parent digoxin was produced 6 and 24 h following LPS treatment compared to the saline controls. Digoxin disposition was similarly altered in mdr1a(+/+) mice but not in mdr1a(-/-) mice 24 h after administering LPS i.c.v. 3. In male rats, the biliary elimination of parent digoxin was reduced at 24 h (60%) and 48 h (40%) after LPS treatment and was blocked by the P-gp substrate cyclosporin A. An observed loss in CYP3A1/2 protein and organic anion transporting polypeptide 2 mRNA in the liver may make a minor contribution to digoxin elimination in male rats after LPS treatment. 4. Conditions which impose inflammation in the CNS produce dynamic changes in mdr1a/P-gp expression/function that may alter hepatic drug elimination and the movement of drugs between the brain and the periphery. The use of experimental models of brain inflammation may provide novel insight into the regulation of P-gp function in that organ.
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PMID:Downregulation of mdr1a expression in the brain and liver during CNS inflammation alters the in vivo disposition of digoxin. 1274 21

P-glycoprotein (PGP) encoded by the Mdr1 gene mediates the excretion of drugs in organs such as the liver and kidney. Inflammation has been shown to suppress the expression and activity of PGP in rodent liver, thus potentially altering the pharmacokinetics of drugs that are substrates of PGP. Here we examined the effect of endotoxin (lipopolysaccharide; LPS)-induced inflammation on the disposition of the PGP substrate doxorubicin (DOX) in the mouse. Male CD-1 mice received 5 mg/kg LPS intraperitoneally. DOX (5 mg/kg) was administered intravenously 24 h after LPS treatment. The time course of DOX levels in plasma, urine, bile, and tissues was analyzed by high performance liquid chromatography. PGP protein and mRNA expression in liver and kidney was measured using Western blots and reverse transcriptase polymerase chain reaction. As compared to controls, LPS-treated mice exhibited a significant decrease (50%) in biliary clearance and 3-fold increased renal clearance of DOX. These changes were associated with strongly reduced PGP protein levels (30% controls, p < 0.05) in the liver and increased PGP levels in the kidney (140% controls, p < 0.05). Hepatic mRNA levels of all Mdr isoforms were reduced in LPS-treated mice, whereas renal Mdr1b levels were increased. In LPS-treated mice, we also measured an increased area under the plasma concentration-time curve and reduced systemic clearance of DOX, as well as a 2- to 5-fold increase in the urinary excretion of the doxorubicin and doxorubicinol aglycones. Our data suggest that endotoxin-induced inflammation in mice causes differential regulation of PGP in liver and kidney, thereby altering the clearance profile of DOX.
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PMID:Impact of endotoxin-induced changes in P-glycoprotein expression on disposition of doxorubicin in mice. 1577 72

We encountered two cases of pediatric living-related liver transplant recipients who showed increases in blood concentration of cyclosporine or tacrolimus, a dual substrate for cytochrome P450 (CYP) 3A and P-glycoprotein (P-gp), during a diarrheal episode. To investigate the effect of intestinal inflammation on the metabolic and efflux pump activities, we conducted the experiments using the lipopolysaccharide (LPS)-induced intestinal damage model. Intestinal epithelial CYP3A activity was assessed by nifedipine oxidation using intestinal epithelial microsomes in rat. Drug efflux by P-gp was tested using digoxin flux with the excised intestine perfusion system in rats. Intraperitoneal injection of LPS (0.3 mg/kg) significantly reduced the intestinal epithelial CYP3A activity by 41% (p < 0.01). In the proximal jejunal segment of the rats treated with LPS, mucosal to serosal flux of digoxin was significantly enhanced compared to that of control (p < 0.05). Efflux of digoxin, which was taken up by intestinal epithelium, to mucosal perfusate was significantly blunted in the jejunum treated with LPS (p < 0.05), which indicates that the LPS treatment reduced the P-gp activity in rat small intestine. These findings suggest that the suppression of CYP3A and P-gp activities may be involved in the mechanism of elevated blood concentrations of cyclosporine and tacrolimus during enteritis-induced diarrhea. To prevent a drug-induced adverse effect, dose of a drug, which is a substrate of CYP3A or P-gp, should be reduced during such an episode.
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PMID:Elevated blood concentrations of calcineurin inhibitors during diarrheal episode in pediatric liver transplant recipients: involvement of the suppression of intestinal cytochrome P450 3A and P-glycoprotein. 1591 Mar 87

At the blood-brain barrier, P-glycoprotein, an ATP-driven drug efflux pump, selectively limits drug access to the brain parenchyma, impeding pharmacotherapy of a number of central nervous system (CNS) disorders. We previously used confocal imaging to demonstrate in isolated rat brain capillaries that endothelin-1 (ET-1), acting through an ET(B) receptor, NO synthase, and protein kinase C, rapidly and reversibly reduces P-glycoprotein transport function. In this study, we define a link between the brain's innate immune response and functional regulation of P-glycoprotein. We show that exposing brain capillaries to the inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha), activated a TNF-R1 receptor, released ET-1, activated ET(B) receptor signaling, and essentially abolished P-glycoprotein-mediated transport. Bacterial lipopolysaccharide, a potent activator of the brain's innate immune response, reduced P-glycoprotein activity through TNF-alpha release, ET-1 release, and ET(B) receptor signaling. TNF-alpha and LPS effects had a rapid onset (minutes), were reversible, and did not involve changes in tight junctional permeability. These findings define a signaling pathway through which P-glycoprotein activity is acutely modulated. They show that this key component of the selective/active blood-brain barrier is an early target of cytokine signaling during the innate immune response and suggest ways to manipulate the barrier for improved CNS pharmacotherapy.
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PMID:Rapid modulation of P-glycoprotein-mediated transport at the blood-brain barrier by tumor necrosis factor-alpha and lipopolysaccharide. 1627 73

Recent advances in pharmacogenomics have suggested the association of clinical outcome of glucocorticoid-based anti-inflammatory therapy with a single nucleotide polymorphism at position 3435 in exon 26 (C3435T) of the MDR1 gene. In the present study, the effects of the MDR1 C3435T genotype on the time-dependent profiles of gene expression and function of MDR1/P-glycoprotein were evaluated in peripheral blood mononuclear cells (PBMCs) under lipopolysaccharide (LPS)-induced experimental acute inflammation. LPS treatment resulted in the rapid elevation of IL-1beta and TNF-alpha mRNA levels relative to beta-actin mRNA at 1 h, with a subsequent slight decrease at 3 h after the treatment, while the down-regulation of the relative concentration of MDR1 mRNA was found at 3 h, not at 1 h, after LPS treatment. Here, the C3435T genotype-dependent down-regulations of MDR1 mRNA level were found for CC(3435) and CT(3435), but not for TT(3435), and were 64.1+/-10.1%, 71.4+/-5.9% and 100.0+/-22.5% (+/-S.D.), respectively, of their respective baseline levels, which were independent of C3435T (0.010+/-0.005, 0.011+/-0.013 and 0.009+/-0.006 (+/-S.D.), respectively). The C3435T genotype-dependent down-regulation was supported by the increase of the intracellular accumulation of calcein in PBMCs treated with LPS for 72 h, and the increase was more predominant for CC(3435) than TT(3435). These data suggested that glucocorticoid-based anti-inflammatory therapy might be more effective for C(3435)-allele carriers than non-carriers.
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PMID:Genotype-dependent down-regulation of gene expression and function of MDR1 in human peripheral blood mononuclear cells under acute inflammation. 1685 22

1. The aim of the present study was to examine the effect of bacterial lipopolysaccharide (LPS) on the disposition of an organic anion transporting polypeptide and P-glycoprotein substrate in the rat isolated perfused liver. 2. Male Sprague-Dawley rats were divided into four groups. Three of the groups received 1, 2.5 or 5 mg/kg, i.p., Escherichia coli LPS in sterile saline. The fourth group received an equivalent volume of sterile saline i.p. Twenty-four hours after treatment, rats were anaesthetized and the liver isolated and perfused with fexofenadine at an initial concentration of 2000 ng/mL in a recirculating system. Perfusate and bile samples were collected for 60 min and the liver was collected at the end of the perfusion. Fexofenadine concentrations were determined by HPLC. Fexofenadine pharmacokinetic parameters, the final liver : perfusate (L : P) and bile : liver (B : L) concentration ratios were determined. 3. Injection of LPS changed the hepatic disposition of fexofenadine. The changes were most marked in the 5 mg/kg LPS group. Notably, clearance from the perfusate (CL) and into the bile (CLB; 5.9 +/- 0.6 and 1.24 +/- 0.20 mL/min, respectively), L : P (44 +/- 11) and B : L (17 +/- 2) were all reduced (P < 0.05) in this group compared with control (CL 10.0 +/- 1.1 mL/min; CLB 2.7 +/- 0.5 mL/min; L : P 87 +/- 14; and B : L 30 +/- 4). 4. In conclusion CL and CLB were reduced following treatment with LPS in a manner consistent with downregulation of both canalicular and sinusoidal transport.
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PMID:Alteration of fexofenadine disposition in the rat isolated perfused liver following injection of bacterial lipopolysaccharide. 1689 40


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