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)

The impact of the novel chemosensitizer ((2-isopropyl-1-(4-[3-N-methyl-N-(3,4-dimethoxy-beta- phenethyl)amino]propyloxy)benzenesulfonyl))indolizine (SR33557) on the intracellular distribution of doxorubicin (DOX) within the multidrug-resistant murine P388/ADR leukemia cell line was studied by fluorescence microscopy. We found that under conditions which modulated multidrug-resistant (30 microM SR33557 for 1 h), P388/ADR cells presented an original sequestration of DOX in large intracellular vesicles, where SR33557 is itself sequestered, as seen by colocalization studies. Colocalization experiments with lysosomal and mitochondrial probes suggest that these vesicles are neither mitochondrial in nature nor functional lysosomes. To investigate the biochemical basis for this effect, we studied the impact of SR33557 on the sphingolipid metabolism of P388/ADR cells. We observed that although P388/ADR cells normally catabolized exogenous [3H]sphingomyelin, when pretreated with SR33557 they showed almost complete inhibition of sphingomyelin breakdown. Finally, in order to demonstrate that the inability of P388/ADR cells to degrade sphingomyelin in the presence of SR33557 (which is a potent inhibitor of acid lysosomal sphingomyelinase) leads to phospholipid accumulation, we performed electron microscopy where we observed laminated inclusions. These morphological modifications are similar to those observed in Niemann-Pick disease lymphoblastoid cell lines which are inherently deficient in acid sphingomyelinase activity. The observation that, in the absence of SR33557, these Niemann-Pick disease cell lines presented similar DOX sequestration to that of SR33557-treated P388/ADR cells strongly suggests that DOX accumulates in SR33557-induced myeloid bodies. The redistribution of DOX within these vesicles, perhaps by preventing its expulsion by P-glycoprotein, may be a key in discovering the mechanism of action of SR33557.
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PMID:Modulation of subcellular distribution of doxorubicin in multidrug-resistant P388/ADR mouse leukemia cells by the chemosensitizer ((2-isopropyl-1-(4-[3-N-methyl-N-(3,4-dimethoxy-beta- phenethyl)amino]propyloxy)-benzenesulfonyl))indolizine. 142 91

Progesterone inhibits intracellular transport of lysosomal cholesterol in cultured cells, and thus at least in part mimics the biochemical phenotype of Niemann-Pick type C disease (NPC) in human fibroblasts. The goal of this study was to determine whether metabolism of progesterone to other steroids is affected by the NPC mutation or by P-glycoprotein (a known progesterone target). We found that human fibroblasts metabolize progesterone in three steps: rapid conversion to 5alpha-pregnane-3,20-dione, which is then reduced to 5alpha-pregnane-3beta(alpha)-ol-20-one with subsequent 6alpha-hydroxylation. The pattern and rates of progesterone metabolism were not significantly different in a variety of fibroblasts from normal individuals, NPC patients, and obligate heterozygotes. Inhibition of steroid 5alpha-reductase with finasteride completely blocked metabolism of progesterone but had no effect on inhibition of LDL-stimulated cholesterol esterification (IC50 = 10 microM). Progesterone also partially inhibited 25-hydroxycholesterol-induced cholesterol esterification, with similar dose-dependence in normal and NPC fibroblasts. P-glycoprotein levels varied significantly among the various fibroblasts tested, but no correlation with NPC phenotype or rate of progesterone metabolism was noted, and P-glycoprotein inhibitors did not affect conversion of progesterone to products. These results indicate that metabolism of progesterone in human fibroblasts is largely independent of its ability to interfere with cholesterol traffic and P-glycoprotein function.
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PMID:Progesterone metabolism in human fibroblasts is independent of P-glycoprotein levels and Niemann-Pick type C disease. 1062

It remains controversial whether deficiency of the Niemann-Pick C1 (npc1) protein results in altered cholesterol signaling at the endoplasmic reticulum (ER). In this report, we have measured the processed, nuclear form of sterol regulatory element binding protein (SREBP)-1 in livers of npc1 wild-type, heterozygous, and homozygous deficient mice, alone, and in combination with deficiencies of the low density lipoprotein receptor (LDLR) or the multiple drug resistant (mdr)1a, P-glycoprotein. Cleavage of SREBPs to activated forms normally occurs when the ER is deficient in cholesterol. A large decrease in processed SREBP-1 was evident in fasted npc1(-/-) mice and npc1(-/-), mdr1a(-/-) mice, with no decrease evident in npc1(-/-), LDLR(-/-) mice. These results suggest that the increase in cellular cholesterol which occurs in npc1(-/-) and in npc1(-/-), mdr1a(-/-) mice includes the sites responsible for cholesterol signaling, while the similar increase in cholesterol found in npc1(-/-), LDLR(-/-) mice does not.
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PMID:Cholesterol signaling at the endoplasmic reticulum occurs in npc1(-/-) but not in npc1(-/-), LDLR(-/-) mice. 1139 80

Niemann-Pick type C disease is a progressive neurological disease with cholesterol storage in liver, and npc1-/- mice share these features and are sterile. We have searched for the cause of sterility and found normal folliculogenesis and progesterone levels but lack of implantation. Multiple drug resistance (MDR) P-glycoproteins are plasma membrane proteins implicated in the movement of drugs and lipids across membranes. Their functions are inhibited by progesterone, which has been shown to alter cellular cholesterol homeostasis and has implicated P-glycoproteins in the movement of cholesterol to the endoplasmic reticulum. We have introduced the mdr1a knockout into the npc1 mutant line. While the neurological disease continues at its usual rate, preventing the females from taking care of their litters, npc1-/-, mdr1a-/- females became fertile. Although the mdr1a P-glycoprotein co-localizes with caveolae, neither caveolin-1 nor npc1 levels were significantly altered in the livers of double homozygotes. The absence of mdr1a was confirmed by immunoblotting, but npc1 deficiency was not associated with consistent changes in cerebellar mdr1a in mdr1a+/+ mice. The results show that a mdr1a mutation is an in vivo suppressor of female sterility in npc1 deficient mice.
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PMID:mdr1a deficiency corrects sterility in Niemann-Pick C1 protein deficient female mice. 1198 26

Disposition of the lipid-lowering agent ezetimibe (EZ) and its glucuronide (GLUC), which is mainly formed by UDP-glucuronosyltransferase (UGT) 1A1, is influenced by the intestinal efflux transporters P-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP) 2. To evaluate the role of Mrp2 in overall disposition and pharmacodynamic effects of EZ, wild-type and Mrp2-deficient (TR-negative) Lewis.1W rats (eight males each) fed with a cholesterol-enriched diet were orally treated with 5 mg/kg EZ for 14 days. EZ and GLUC in serum, urine, and feces, and cholesterol, campesterol, and sitosterol in serum, were assayed using liquid chromatography (LC)-tandem mass spectrometry and LC-mass spectrometry methods, respectively. Gene expression of Bsep (bile salt exporting pump), multidrug resistance (Mdr) 1a, Mdr1b, Mrp2, Mrp3, Ntcp (sodium taurocholate co-transporting polypeptide), organic anion transporting polypeptides (Oatp) 1, 2, 4, and Ugt1a1 was quantified in several tissues using real-time reverse transcription-polymerase chain reaction. Mrp2 deficiency resulted in lower serum levels and fecal excretion of EZ (1.4 +/- 0.4 versus 3.1 +/- 1.1 ng/ml; 115 +/- 48 versus 361 +/- 102 microg/day, both p < 0.01), whereas serum concentrations of GLUC were manyfold increased compared with wild type (196 +/- 76 versus 23 +/- 25 ng/ml; p < 0.01), associated with elevated renal excretion and decreased intestinal clearance (7.8 +/- 3.1 versus 0.4 +/- 0.4 microg/day, p < 0.01; 0.3 +/- 0.3 versus 15 +/- 17 ml/min; p < 0.05). The sterol-lowering effect of EZ was reduced in correlation to EZ serum levels (cholesterol: r = 0.449, p = 0.093; campesterol: r = 0.717, p = 0.003; sitosterol: r = 0.507, p = 0.054), whereas GLUC was inversely correlated (r = -0.743, p = 0.002; r =-0.768, p = 0.001; r =-0.634, p = 0.011). Disposition of EZ may have been additionally influenced by hepatic P-gp, Mrp3, and Ugt1a1, which were expressed significantly higher in Mrp2-deficient rats. Mrp2 deficiency in rats is associated with decreased sterol-lowering effect of ezetimibe, obviously caused by lower intestinal clearance of the glucuronide and decreased enterosystemic and enterohepatic recycling of the parent ezetimibe to the intestinal Niemann-Pick C 1-like 1 sterol-uptake compartment.
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PMID:Disposition and sterol-lowering effect of ezetimibe in multidrug resistance-associated protein 2-deficient rats. 1677 39