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

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

To evaluate the significance of P-glycoprotein (P-gp)-mediated active efflux on the blood-brain barrier (BBB) permeability of cyclosporin A (CsA) in vivo, we investigated the effects of ATP depletion in the brain and of a multidrug-resistant (MDR) reversing agent on the transport of CsA across the BBB. Using transient brain ischemia obtained by 4-vessel occlusion of vertebral and common carotid arteries in rats to deplete ATP content in the brain, the estimated permeability surface area product (PS) value of [3H]CsA was increased 2.7-fold compared with that in normal rats, whereas the PS value of [14C]sucrose was not altered. Additionally, when quinidine hydrochloride (QND) was infused into the brain through a microdialysis probe implanted in the rat hippocampus, the extravascular extraction of CsA was increased to approximately 2.5-fold of the control, whereas no difference in the extravascular extraction between control and normal rats having no implanted dialysis probe was observed. Furthermore, the efflux rate from brain to blood of CsA was decreased remarkably to 5% of control at steady-state by co-administration of CsA with QND directly into the brain through the dialysis probe. The ATP-dependent and QND-sensitive efflux of CsA from the brain strongly indicates that P-gp in the brain capillary endothelial cells functions as an efflux pump under the physiological state, and that P-gp-mediated efflux of CsA is a major mechanism of the restricted transfer from blood into the brain.
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PMID:In vivo evidence for ATP-dependent and P-glycoprotein-mediated transport of cyclosporin A at the blood-brain barrier. 798 14

The transport of drugs into the brain is prevented in most cases by the presence of the blood brain barrier (BBB). Endothelial cells in the brain of vertebrates are fused together by tight junctions that eliminate the normal pathways of free diffusion existing in the capillary beds of organs other than the brain or spinal cord. Therefore, a molecule that has a molecular weight less than a 500 Dalton can cross the BBB in proportion to lipid solubility. Recent molecular biological studies have contributed to the isolation and functional analysis of transporter proteins at the BBB. There are three types of endogenous transport systems: carrier-mediated transporters, active efflux transporters such as P-glycoprotein, and receptor-mediated transcytosis systems. The structural and functional integrity of the BBB has appeared to be dramatically altered by various diseases of the CNS such as ischemia, anoxia and inflammation, resulting in cerebral edema and damage to the neurons. General anesthetic agents can alter the BBB function. For example, the degree of the BBB disruption was smaller during isoflurane anesthesia than during pentobarbital anesthesia. In this review, we focus on recent progress in the BBB research and functional modulation produced by general anesthetics.
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PMID:[Blood-brain barrier and general anesthetics]. 1367 73

Ischemia-reperfusion injury is an unavoidable problem for organ transplantation including small bowel transplantation, and causes a large intra-individual variation of tacrolimus (FK506) pharmacokinetics. Little information is available about the regulation of the intestinal P-glycoprotein expression during tissue regeneration. In the present study, we have examined the molecular and functional variations of ileum P-glycoprotein using rats after ischemia-reperfusion treatment. Morphological study revealed a rapid regeneration of the intestinal wall during 24 h after reperfusion. A reverse transcription-coupled competitive PCR and Western blot analysis revealed that the intestinal expression of P-glycoprotein recovered with time after reperfusion. At 24 h after reperfusion, the ileum P-glycoprotein level was transiently increased to two-fold, and the absorption rate of dihydro-[(3)H]FK506 from in situ ileum loop into portal vein was markedly low in comparison with the control. P-glycoprotein was detected in the crypt area as well as in villous cells at 6 h after reperfusion, and then localized to the apical surface at 24 h consistent with the cell proliferation and differentiation. However, the P-glycoprotein level returned to normal at 48 h. The intra-individual variation in the absorptive rate of tacrolimus was suggested to be regulated by the morphological status of the intestinal epithelium and enterocyte expression level of P-glycoprotein. Therefore, the monitoring of the enterocyte P-glycoprotein level would provide useful information for determining the dosage of tacrolimus immediately after small bowl transplantation.
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PMID:Transient up-regulation of P-glycoprotein reduces tacrolimus absorption after ischemia-reperfusion injury in rat ileum. 1567 May 75

We previously established a in vitro system for assessing early ischemia/reperfusion injury using monolayers of human intestinal epithelial cell line Caco-2, in which lipid peroxidation caused by tertiary-butylhydroperoxide (t-BuOOH), a lipid peroxidation inducer, acts as a trigger of the injury. By now, we have shown that superoxide anion participates in the opening of tight junctions (TJ) induced by reoxygenation following the induction of lipid peroxidation by t-BuOOH at a low concentration. The present objectives are to elucidate the dysfunction of P-glycoprotein (P-gp) in addition to the opening of TJ by t-BuOOH at a high concentration condition using rhodamine123 (Rho123) as a P-gp substrate and cyclosporine A (CyA) as a P-gp inhibitor. Also, we compared the inhibition effect of lutein and other compounds such as biliverdin as a radical scavenger on the opening of TJ and the dysfunction of P-gp. t-BuOOH at a high concentration increased the permeability of Rho123 in the apical to basal direction and decreased basal to apical direction when compared with control conditions. t-BuOOH at a high concentration showed no significant difference between directional transport of Rho123 and no inhibition was observed in the permeability of both directions by CyA. The staining intensity of Western blot was decreased by t-BuOOH at a high concentration. Although lutein and the other compounds had recovery effects on the opening of TJ and P-gp dysfunction induced by t-BuOOH, lutein is more advantageous than other compounds since it has effective effects at the lower concentration. In conclusion, the barrier dysfunction such as the inhibition of P-gp in addition to the opening of TJ was induced by t-BuOOH at a high concentration condition. The above two barrier dysfunctions was ameliorated by antioxidant such as lutein and biliverdin.
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PMID:Ischemia/reperfusion injury in the monolayers of human intestinal epithelial cell line caco-2 and its recovery by antioxidants. 1685 27

We have recently reported that in chronic myocardial ischemia, adult mammalian cardiomyocytes express P-glycoprotein (P-gp). We now investigate if P-gp is also expressed in acute regional ischemia followed by reperfusion. Adult conscious sheep underwent 12-min occlusion of the mid-left anterior descending artery (inflatable cuff). Successful ischemia-reperfusion was confirmed by monitoring percent systolic left ventricular anterior wall thickening (sonomicrometry) during the whole ischemic period and every 10 min over 2 hr following cuff deflation. At 3, 24, and 48 hr after reperfusion, P-gp expression was investigated by immunohistochemistry and Western blot and MDR-1 mRNA by RT-PCR. Cardiomyocytes in the occluded artery territory (but not those in remote areas) consistently expressed P-gp at their sarcolemma. Whereas at 3 and 24 hr P-gp was mainly observed in the T tubules, at 48 hr it predominated in intercalated discs and gap junctions. RT-PCR and Western blot revealed higher expression in ischemic than in control myocardium. We conclude that in adult sheep with acute myocardial ischemia, the MDR-1 gene-encoded P-gp is expressed at the sarcolemma of the cardiomyocytes from 3 hr up to at least 48 hr after reperfusion.
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PMID:Expression of the MDR-1 gene-encoded P-glycoprotein in cardiomyocytes of conscious sheep undergoing acute myocardial ischemia followed by reperfusion. 1710 27

Neuronal damage after stroke-associated brain hypoxia is a leading cause of long-term disability and death. The refractoriness to therapeutic strategies for neuroprotection after 3 h post brain ischemia is poorly understood. P-glycoprotein (P-gp), the multidrug resistance gene (MDR-1) product is normally expressed at blood-brain-barrier. P-gp neuronal expression has been demonstrated in refractory epilepsy and after brain ischemia. In this report we investigated the hypoxia-induced neuronal P-gp expression after local injection of CoCl(2) (1-200 mM) in the fronto-parietal cortex of male adult rats (Bregma -1.30 mm) by stereotaxic surgery. P-gp immunostaining of brain slides was analyzed using specific monoclonal antibodies and double immunolabeling was done with specific astrocytic and neuronal markers. Five days after injection of 1 mM CoCl(2), P-gp expression surrounding the lesion site was observed in neurons, astrocytic end-foot on capillary blood vessels and endothelial cells on blood vessels. Higher CoCl(2) doses (200 mM) resulted in additional P-gp immunostaining of the entire astrocytic and neuronal cytoplasm. Electron microscopy (EM) studies showed alterations in neurons as early as 6 h after the CoCl(2) injection. P-gp expression in hypoxic neurons and astrocytic end-foot could potentially impair of drugs access to the brain parenchyma thus suggesting the presence of two P-gp-based pumping systems (one in astrocytes and other in the hypoxic neurons) that are able to behave as a previously unnoticed obstacle for pharmacological strategies of neuroprotection.
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PMID:Neuronal mdr-1 gene expression after experimental focal hypoxia: a new obstacle for neuroprotection? 1745 14

For drug absorption, intestinal drug permeability's through both the paracellular and transcellular routes were analyzed. Absorption enhancers, such as sodium caprate (C10), decanoylcarnitine (DC) and tartaric acid (TA), increased the paracellular permeability of water-soluble, low lipophilic and poorly absorbable drugs by enlargement of tight junction (TJ) adhering to the intercellular portion; that is, expansion of the paracellular routes. C10 increased the intracellular calcium level to induce contraction of calmodulin-dependent actin filaments. Although DC also increased the intracellular calcium level, the action was independent of calmodulin, and thus the action mechanism of DC was considered to differ from that of C10. DC and TA decreased the intracellular ATP level and the intracellular pH, suggesting that intracellular acidosis increases the calcium level through decrease in ATP level followed by opening TJ. TA had no effect on Western blot analysis, but TA significantly inhibited excretion of rhodamine 123, one of the P-glycoprotein (P-gp) substrates, from the serosal to mucosal side, suggesting that TA increases the intestinal absorption of P-gp substrates, possibly by inhibiting the P-gp function without changing the expression of P-gp. During ischemia/reperfusion (I/R) injury during small intestine grafting, TJ opening and decrease in P-gp function simultaneously occurred. The in vitro model of I/R showed that lipid peroxidation is a trigger of the injury, and superoxide and iron ion participate in TJ opening and decrease in P-gp function. Colonic epithelial cells have the specific transcellular transport systems for lipopolysaccharide (LPS), one of which shows substrate specificity in the interaction with CD14 and/or that of TLR4. In the infective disease induced by LPS, the mucosal LPS sensitive transport capability was decreased and in the secretory direction, the receptor-mediated uptake mechanism disappeared. LPS taken up into the cells can be excreted by P-gp or mrp. The expression levels and function of the secretory transporters were considered to be increased in the infective condition. In conclusion, changes in TJ as the membrane structure and P-gp as the membrane function are important factors controlling intestinal membrane transport.
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PMID:Mechanistic analysis for drug permeation through intestinal membrane. 1749 13

The multidrug resistance gene 1 product, P-glycoprotein (P-gp), is expressed in several excretory organs, including the apical membrane of proximal tubules. After inducing acute renal failure, P-gp expression is upregulated and this might be a protective function by pumping out toxicants and harmful products of oxidative stress. We characterized renal function of P-gp knockout mice and studied its consequences in renal ischemic damage. Compared with wild-type mice, knockout mice have a lower glomerular filtration rate and renal plasma flow. An augmented urinary excretion of sodium, numerous amino acids, calcium, glucose, and low molecular weight proteins was observed along with an increased diuresis. A higher lithium plasma clearance in the knockout mice suggested proximal tubular dysfunction. Electron microscopy showed mitochondrial abnormalities in proximal tubular cells that could account for decreased adenosine triphosphate levels in the cortex. After inducing ischemia, wild-type mice showed a decrease in creatinine clearance and severe proximal tubular necrosis. In contrast, knockout mice had no signs of tubular damage. Our data indicate that P-gp knockout mice have impaired renal function but are protected against ischemic renal injury.
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PMID:P-glycoprotein-deficient mice have proximal tubule dysfunction but are protected against ischemic renal injury. 1785 69

The present study was carried out in order to identify the changes in expression of multidrug resistance-associated protein (Mrp) 2 and P-glycoprotein (P-gp) in the intestine and remote organs after intestinal ischemia-reperfusion (I/R). Mrp2 expression in the jejunum and liver was decreased at 6 h after I/R. This decrease in Mrp2 expression was associated with an increase in the serum level of IL-6. These results suggest that the decreased Mrp2 expression after intestinal I/R was regulated by IL-6. The expression level of mdr1a in the ileum, which encodes P-gp, was decreased at 6 and 24 h after I/R, and the expression level of mdr1b, also encodes P-gp, was not altered at any time. P-gp protein expression in the ileum was decreased at 6 h after I/R. In the liver, mdr1a expression was decreased at 6 h after I/R, but mdr1b expression was increased at 6 h after I/R. P-gp protein was not altered at any time. In the kidney, mdr1a expression was decreased at 24 h after I/R, but mdr1b expression was not altered at any time. P-gp protein expression in the kidney was decreased at 24 h after I/R, as was mdr1a expression. These results suggest that P-gp expression after intestinal I/R differs in each organ. This is the first report to provide evidence that expression levels of transporters in remote organs are altered intestinal after I/R.
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PMID:Alteration of Mrp2 and P-gp expression, including expression in remote organs, after intestinal ischemia-reperfusion. 1853 50

The bioavailability of orally administrated cyclosporine A (CsA) is poor and variable in liver transplantation recipients. Little information is available about the effect of liver ischemia-reperfusion (I/R) injury, which is associated with liver transplantation, on the intestinal first-pass metabolism of CsA. In the present study, we investigated the pharmacokinetics of CsA after liver I/R and assessed the effect of liver I/R via CYP3A and P-glycoprotein (P-gp) on its intestinal first-pass metabolism. When CsA alone was administrated orally, the area under the concentration-time curve (AUC) in the I/R rats was significantly decreased compared with that in the sham rats. On the other hand, there were no significant differences in the AUC between I/R and sham rats when CsA was administrated intravenously or orally with ketoconazole. After intraloop administration of CsA to the small intestine (upper, middle, and lower portions) of the I/R and sham rats, the AUC(0-15 min) in the upper intestine was significantly lower in the I/R rats than in the sham rats. CYP3A activity and the expression levels of P-gp in the upper intestine of the I/R rats were significantly higher than those of the sham rats. Our study clearly demonstrates for the first time that liver I/R decreases the oral bioavailability of CsA and that this is attributable principally to increased first-pass metabolism mediated by CYP3A and P-gp in the upper small intestine. The present findings provide useful information for the etiology of liver I/R injury and appropriate use of CsA after liver transplantation.
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PMID:Decreased oral absorption of cyclosporine A after liver ischemia-reperfusion injury in rats: the contribution of CYP3A and P-glycoprotein to the first-pass metabolism in intestinal epithelial cells. 1884 3


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