Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Over-expression of the MDR-1 gene, which codes for P-glycoprotein, is thought to be an important mechanism in the drug resistance exhibited by many tumours. A number of chemotherapeutic agents which induce MDR-1 expression are also components of combination chemotherapies that are used in the treatment of high grade non-Hodgkin's lymphomas (NHL). We have therefore examined expression of MDR-1 in a series of NHL by Northern blot analysis as well as investigated the localization of P-glycoprotein by immunohistochemistry. The series included 11 hyperplastic reactive nodes and tonsils, 17 low grade NHL and 15 high grade NHL. The levels of MDR-1 mRNA were quantified by scanning densitometry and comparison with levels of glucose-6-phosphate dehydrogenase (G6PD). The MDR-1 mRNA was observed in both non-malignant and NHL tissues. Immunohistochemical staining revealed that expression of MDR-1 mRNA in reactive nodes was related to the presence of P-glycoprotein in lymphocytes, however, P-glycoprotein was apparent in both the reactive lymphocytes and tumour cells in the NHL samples. Elevated mRNA levels (2-3 fold increase) were observed in some low grade and high grade NHL relative to those observed in reactive lymphoid tissue. There appeared to be little correlation, however, between expression of the MDR-1 gene and either treatment intensity or response to therapy. The drug resistance that is often encountered in NHL patients is therefore likely to involve mechanisms other than over-expression of P-glycoprotein.
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PMID:MDR-1 expression in non-Hodgkin's lymphomas is unrelated to treatment intensity or response to therapy. 853 96

A major obstacle to successful cancer chemotherapy is the development of multidrug resistance (MDR). The previous study revealed that a doxorubicin-resistant AML subline (AML-2/DX100) overexpressed an MDR-associated protein (MRP) but not P-glycoprotein. The AML-2/DX100 also showed various levels of resistance to daunorubicin and vincristine but was paradoxically sensitive to hydrogen peroxide (5-fold), t-butyl hydroperoxide (3-fold), and paraquat (2-fold) when compared to the drug-sensitive parental AML-2 cells (AML-2/WT). We compared the activities of antioxidant enzymes to detoxify reactive oxygen species (ROS), including superoxide dismutases, glutathione S-transferase, catalase, glutathione reductase, glutathione peroxidase, and glucose-6-phosphate dehydrogenase in both AML-2/WT and AML-2/DX100. Interestingly, of these antioxidant enzymes, catalase activity of AML-2/DX100 decreased significantly to about one-third that of AML-2/WT (P < 0.000005). The decreased activity of catalase was due to reduced expression of the catalase gene; confirmed by Western blot and reverse transcription-polymerase chain reaction (RT-PCR) analyses. The decreased activity of catalase was maintained even in the absence of doxorubicin for 3 months as well as by the treatment of probenecid, an MRP inhibitor. In addition, there was no difference in catalase activity between HL-60 and another MRP-overexpressing subline HL-60/Adr. Taken together, the paradoxical increase in the sensitivity of an MRP-overexpressing AML-2/DX100 in response to peroxides and paraquat is due to the down-regulation of catalase gene expression, which totally independent of overexpression of MRP. It is therefore possible that decreased catalase activity could be exploited as an Achilles' heel in resistant cells such as this.
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PMID:Down-regulation of catalase gene expression in the doxorubicin-resistant AML subline AML-2/DX100. 1117 67

Zinc, at low levels, has several basic housekeeping functions in metalloenzymes, transcription factors, immunoregulation, growth, and cytoprotection, displaying antioxidant, anti-apoptotic, and anti-inflammatory roles. At high levels, however, the metal can be highly toxic. The aim of this work is to investigate the toxic effect of zinc on antioxidant status and stress proteins in the gills of the brown mussel Perna perna exposed for 48 h to zinc chloride (zinc) at 10, 30 and 100 microM. Glutathione reductase (GR) activity was drastically reduced at 30 and 100 microM zinc. At the lower levels, i.e. 10 microM zinc, antioxidant defenses were up-regulated, as were glutathione levels and the activities of glutathione peroxidase and catalase, in spite of the absence of effect on glutathione S-transferase and glucose 6-phosphate dehydrogenase activity. At the higher tested concentration of 100 microM zinc, oxidative stress was apparent as reflected by the increased lipid peroxidation end products and decreased protein thiol and glutathione levels, associated with an inability to up regulate antioxidant defenses. Using 30 microM zinc, higher gill rhodamine B efflux was observed, indicating an activation of multixenobiotic resistance (MXR) activity, which is reinforced by increased immunoreactive P-glycoprotein detection. Zinc also increased the HSP60-immunoreactive protein, whereas the HSP70-immunoreactive protein remained unchanged. Overall, the results indicate that zinc toxicity -- at higher levels -- may be connected to a strong inhibition of GR activity, and related to the pro-oxidative state found. Mussels showed an adaptive-like response to 10 microM zinc by increasing antioxidant defenses. Increased P-glycoprotein and HSP60 expression, and rhodamine B efflux were also remarkable features in the gill response to zinc.
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PMID:Antioxidant status and stress proteins in the gills of the brown mussel Perna perna exposed to zinc. 1656 39