Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.6.1.3 (ATPase)
 65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acquired resistance to cisplatin (cis-diamminedichloroplatinum (II)) has been generated in vitro in the 41M human ovarian carcinoma cell line, established from a previously untreated patient. Three cisplatin-resistant variants were selected at approximately 2, 4 and 6-fold resistance (in terms of 50% inhibitory concentrations), in order to study the underlying mechanisms of acquired cisplatin resistance. Compared to the parent line, platinum accumulation following exposure to equimolar concentrations of cisplatin was on average (across the entire concentration range) 2.9, 3.6 and 4.8-fold lower in the 41McisR2, 41McisR4 and 41McisR6 cell lines, respectively. Thus the difference in uptake corresponded closely with their resistance factor in the three resistant variants. Moreover, a significant reduction in platinum accumulation was observed as early as 5 min after exposure to cisplatin in the 41M vs 41McisR6 cell lines. Platinum accumulation was similar in all cell lines following exposure to equitoxic concentrations (2 h IC50) of cisplatin. Enhanced efflux of drug was not observed between the 41M and 41McisR6 cells. In addition, there was no difference in intracellular glutathione (GSH) levels. Our previous studies have shown no indication of metallothionein involvement and the decrease in cisplatin uptake in the 41McisR6 cells was reflected by a similar reduction in DNA interstrand cross-links (ISC) formation. These results suggest that the mechanism of acquired resistance to cisplatin in the 41McisR6 cell line may be predominantly due to reduced drug uptake. The 41McisR6 cells were not found to be cross-resistant to ouabain, a postulated specific inhibitor of sodium-potassium adenosine triphosphatase (Na+, K(+)-ATPase), suggesting that decreased cisplatin accumulation in these cells is probably not regulated by alterations in their Na+, K(+)-ATPase levels, and Na+ potential across the plasma membrane. Cellular accumulation of a novel class of platinum (IV) ammine/cyclohexylamine dicarboxylates, which exhibit enhanced cytotoxicity over cisplatin and completely circumvent resistance to cisplatin in the 41McisR line, was also examined. The data suggests that increased accumulation of these compounds, as a result of their enhanced lipophilicity, could account for the dramatic increase in their potency over cisplatin.
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PMID:Reduced drug accumulation as a major mechanism of acquired resistance to cisplatin in a human ovarian carcinoma cell line: circumvention studies using novel platinum (II) and (IV) ammine/amine complexes. 145 52

A variety of cellular proteins bind to cellular and viral enhancer elements. One such factor, known as AP-2, is a 52-kDa transcription factor identified by its interaction with the SV40 and metallothionein enhancers. In addition, it has been found that AP-2 binds to the SV40 T-antigen. AP-2 activity is mediated by both the state of cellular differentiation and changes in signal transduction pathways, suggesting a potential role of AP-2 in the regulation of diverse cellular processes. As part of an effort to examine the chromosomal organization of cellular genes encoding transcription factors, we report the mapping of the gene encoding AP-2 to human chromosome 6p22.3-24 by analysis of somatic cell hybrids and in situ hybridization to chromosomes.
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PMID:Localization of the gene for the DNA-binding protein AP-2 to human chromosome 6p22.3-pter. 191 17

In the present in vivo studies the alterations in cation transporting enzymes of the brain, kidney and liver tissues were assessed at intervals between 0 to 48 h after a single, acute (10 mg kg-1, i.p.) dose of cadmium (Cd). The inhibition of Na+-K+-ATPase during the first 24 h does not parallel the changes in K+-PNPPase suggesting differential effects on phosphorylation and dephosphorylation steps of the overall ATPase reaction. Between 30 min to 2 h the inhibition in enzyme activity was steep (27 per cent in brain, 54 per cent in liver) followed by a rapid reversal between 2-6 h. This critical period may correspond to the time of induction of metallothionein. This enzyme reversal was followed by a significant decrease in Na+-K+ ATPase (40-68 per cent) and K+-PNPPase (44-60 per cent) between 24 to 48 h. A similar pattern was observed in Ca2+-ATPase in all the three tissues. A 33 per cent mortality was observed in rats after 48 h of cadmium challenge. Administration of dithiothreitol (DTT, 20 mg kg-1, i.p.) to CdCl2 pretreated rats at 24 h resulted in mortality reduced from 33 per cent to 0 and reversal in the inhibition of Na+-K+-ATPase in brain and kidney and Ca2+-ATPase in brain. Since protection of brain and kidney enzymes by DTT paralleled its protection against Cd toxicity, their inhibition by Cd may, in part, constitute the biochemical basis of Cd toxicity.
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PMID:Protection against cadmium toxicity and enzyme inhibition by dithiothreitol. 255 24

Prolonged cadmium exposure has been associated with proteinuria, calcuria and loss of calcium from bones in humans. Previous studies have shown that kidney uptake of cadmium in vivo results from proximal tubule absorption of the circulating cadmium metallothionein complex (CdMT), and intracellular release of the Cd2+ ion prior to induction of renal metallothionein. Parenteral administration of CdMT has been found to selectively damage the proximal tubule cell lysosome system with development of a tubular proteinuria pattern similar to that observed under chronic exposure conditions. The present studies also demonstrate a concomitant calcuria but no changes in the excretion of other electrolytes or glucose using this model. These marked changes in renal calcium metabolism occurred in the absence of mitochondrial damage, changes in total, Na/K or Mg-stimulated ATPase activities, renal ATP levels, membrane 45Ca2+ transport or overt tubule cell necrosis during an 8 hour period following CdMT injection. Proteinuria and calcuria were prevented by prior zinc induction of the renal MT pool. Data from these studies indicate that renal proximal tubule cell uptake and degradation of the circulating CdMT complex produces both a marked proteinuria and calcuria. The calcuria does not appear to stem from changes in renal energy metabolism or membrane transport of this element but is probably a secondary result of calcium binding to excreted proteins which are increased in urine to a similar extent. The studies also suggest that zinc status and maintenance of the renal ZnMT pool may play an important role in regulating cadmium-induced renal proteinuria and calcuria by preventing Cd2+ perturbation of the proximal tubule cell lysosome system.
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PMID:Mechanism of cadmium-metallothionein-induced nephrotoxicity: relationship to altered renal calcium metabolism. 282 68

Hepatocytes of transgenic mouse fetuses harboring SV40 virus transforming gene sequences in the SV delta e-MGH fusion gene construct 202 driven by the mouse metallothionein (MT-I) enhancer [R. D. Palmiter, H. Y. Chen, A. Messing, and R. L. Brinster (1985) Nature (London) 316, 457-460] were cultured at Day 19 of gestation and established as a differentiated line expressing albumin and alpha-fetoprotein (AFP) mRNAs. Hepatocyte line FMH-202 contains integrated SV40 sequences, expresses SV40 T-antigen genes, and exhibits unlimited growth potential because it has been cultured 18 months without apparent decrease in cell viability or in growth rate that could suggest the occurrence of a crisis period. Immortalized cells multiply in chemically defined medium deficient in arginine with transferrin plus insulin, whereas EGF, insulin, and transferrin are obligatory requirements for fetal or newborn mouse hepatocyte multiplication in primary cultures. Cells did not grow in agar and were not tumorigenic in nude mice. Their immortalized, nonmalignant phenotype was further documented by low saturation densities of confluent monolayers showing no overgrowth, and by growth arrest in the absence of insulin with subsequent induction of DNA synthesis and resumption of cell growth in response to insulin. Thus, it appears that immortalized SV40 T-antigen-expressing hepatocytes are present in the liver of the transgenic mice. However, at later points in liver development the transforming activity of T-antigen becomes apparent and leads to hepatocellular carcinoma formation in vivo.
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PMID:Immortalized differentiated hepatocyte lines derived from transgenic mice harboring SV40 T-antigen genes. 328 99

A high percentage of transgenic mice developing from eggs microinjected with plasmids containing the SV40 early region genes and a metallothionein fusion gene develop tumors within the choroid plexus. A line of mice has been established in which nearly every affected animal succumbs to this brain tumor. Thymic hypertrophy and kidney pathology are also observed in some mice. SV40 T-antigen mRNA and protein are readily detected in affected tissues; however, SV40 T-antigen gene expression is barely detectable in unaffected tissues or in susceptible tissues prior to overt pathology, suggesting that tumorigenesis depends upon activation of the SV40 genes. Comparison of DNA from tumor tissue (or cell lines derived from tumors) with DNA from unaffected tissues reveals structural rearrangements as well as changes in DNA methylation of the foreign DNA. The SV40 genes are frequently amplified in tumor tissue, which further indicates that their expression is intimately involved in tumorigenesis in transgenic mice.
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PMID:Transgenic mice harboring SV40 T-antigen genes develop characteristic brain tumors. 632 63

We examined the role of reactive oxygen metabolites and the protective effect of zinc-induced metallothionein (MT) synthesis on gentamicin nephrotoxicity both in vivo and in vitro. In vivo study we found that the MT content of renal cortex of the zinc preinjected rats was significantly increased, and proximal tubular necrosis and acute renal failure caused by injection of gentamicin were ameliorated. In suspended proximal tubules (PT), Na(+)-K(+)-ATPase activity and DNA synthesis were suppressed by the addition of gentamicin, but in zinc-pretreated rats' PT, these were not suppressed by the addition of gentamicin. Meanwhile MDA and hydroxyl radicals were significantly less in zinc-pretreated rats' PT compared to that in the control. Finally, we found that gentamicin enhanced superoxide anion and hydroxyl radical productin in renal cortical mitochondria. Superoxide anion could be suppressed by SOD and hydroxyl radical could be scavenged by DMSO, DFO and CAT. Our data confirm that hydroxyl radicals play a role in the pathogenesis of gentamicin nephrotoxicity, gentamicin can induce suppression of Na(+)-K(+)-ATPase activity and DNA synthesis in rats' proximal tubules leading to renal injury; this injury may be relevant to reactive oxygen metabolites generated by gentamicin. Renal cortical mitochondria is the source of reactive oxygen metabolites, which induces renal injury, and zinc-induced metallothionein synthesis could ameliorate gentamicin nephrotoxicity via scavenging reactive oxygen metabolites.
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PMID:Mechanism of gentamicin nephrotoxicity in rats and the protective effect of zinc-induced metallothionein synthesis. 780 Feb 47

Bacterial plasmids contain specific genes for resistances to toxic heavy metal ions including Ag+, AsO2-, AsO4(3-), Cd2+, Co2+, CrO4(2-), Cu2+, Hg2+, Ni2+, Pb2+, Sb3+, and Zn2+. Recent progress with plasmid copper-resistance systems in Escherichia coli and Pseudomonas syringae show a system of four gene products, an inner membrane protein (PcoD), an outer membrane protein (PcoB), and two periplasmic Cu(2+)-binding proteins (PcoA and PcoC). Synthesis of this system is governed by two regulatory proteins (the membrane sensor PcoS and the soluble responder PcoR, probably a DNA-binding protein), homologous to other bacterial two-component regulatory systems. Chromosomally encoded Cu2+ P-type ATPases have recently been recognized in Enterococcus hirae and these are closely homologous to the bacterial cadmium efflux ATPase and the human copper-deficiency disease Menkes gene product. The Cd(2+)-efflux ATPase of gram-positive bacteria is a large P-type ATPase, homologous to the muscle Ca2+ ATPase and the Na+/K+ ATPases of animals. The arsenic-resistance system of gram-negative bacteria functions as an oxyanion efflux ATPase for arsenite and presumably antimonite. However, the structure of the arsenic ATPase is fundamentally different from that of P-type ATPases. The absence of the arsA gene (for the ATPase subunit) in gram-positive bacteria raises questions of energy-coupling for arsenite efflux. The ArsC protein product of the arsenic-resistance operons of both gram-positive and gram-negative bacteria is an intracellular enzyme that reduces arsenate [As(V)] to arsenite [As(III)], the substrate for the transport pump. Newly studied cation efflux systems for Cd2+, Zn2+, and Co2+ (Czc) or Co2+ and Ni2+ resistance (Cnr) lack ATPase motifs in their predicted polypeptide sequences. Therefore, not all plasmid-resistance systems that function through toxic ion efflux are ATPases. The first well-defined bacterial metallothionein was found in the cyanobacterium Synechococcus. Bacterial metallothionein is encoded by the smtA gene and contains 56 amino acids, including nine cysteine residues (fewer than animal metallothioneins). The synthesis of Synechococcus metallothionein is regulated by a repressor protein, the product of the adjacent but separately transcribed smtB gene. Regulation of metallothionein synthesis occurs at different levels; quickly by derepression of repressor activity, or over a longer time by deletion of the repressor gene at fixed positions and by amplification of the metallothionein DNA region leading to multiple copies of the gene.
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PMID:Newer systems for bacterial resistances to toxic heavy metals. 784 81

We examined the differential effects of the H-ras oncogene and the K-ras oncogene on cisplatin sensitivity in murine NIH/3T3 cells transfected with these oncogenes. Although the NIH/3T3 cells transformed with H-ras oncogenes (EJ-NIH/3T3 and Ha8-21) showed an increased resistance to cisplatin compared to the parental NIH/3T3, the cell lines transformed with K-ras oncogenes (DT and 1,8DNP2-2-5) did not. Compared with NIH/3T3, the 2 H-ras transformants reduced both the accumulation of cisplatin and the Na+,K(+)-ATPase activity in the membrane fraction. On the other hand, we observed no significant difference in cellular accumulation of cisplatin or in Na+,K(+)-ATPase activity between parental NIH/3T3 and the K-ras transformants. Since these ras transformants did not affect the cellular metallothionein content, transcriptional level of DNA polymerase beta or activity of glutathione-S-transferase which is not associated with cisplatin sensitivity, these results suggest that cisplatin resistance is brought about by the H-ras oncogene, but not by K-ras, and that induction of cisplatin resistance by H-ras is mainly due to a reduction of cisplatin accumulation and an impairment of Na+,K(+)-ATPase activity in the membrane fraction.
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PMID:Differential Na+,K(+)-ATPase activity and cisplatin sensitivity between transformants induced by H-ras and those induced by K-ras. 807 52

We have reported that preinjection of zinc could ameliorate gentamicin-induced nephrotoxicity in vivo via the induction of metallothionein. The present project was designed to study whether preinjection of zinc could protect from the harmful effects of gentamicin on DNA synthesis, Na(+)-K(+)-ATPase activity, and free radical production in rat renal proximal tubules (PT) in vitro. PT were prepared and cultured from normal, saline-preinjected, and Zn-preinjected (Zn 10 mg/k/day s.c. 5 days) Wistar male rats weighing 80-120 g. The results showed that DNA synthesis and Na(+)-K(+)-ATPase activity were significantly suppressed in the normal and saline-preinjected rats' PT by addition of gentamicin to the media in the concentration of 12.4 mg/mL; however, these reactions were not suppressed by gentamicin in Zn-preinjected rats' PT, and malondialdehyde and hydroxyl radical production in Zn-preinjected rats' PT were significantly lower than those in the normal and saline-preinjected rats' PT (p < .01). On the other hand, the metallothionein in Zn-preinjected rats' PT was very significantly higher than that in the normal and saline-preinjected rats' PT (p < .001). Our data indicate that gentamicin-induced suppression of DNA synthesis and Na(+)-K(+)-ATPase activity in rat PT, which lead to renal injury, may be relevant to free radicals generated by gentamicin; and that preinjection of zinc could ameliorate gentamicin-induced nephrotoxicity via the induction of the metallothionein synthesis in rat PT to scavenge free radicals generated by gentamicin.
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PMID:Zinc-induced metallothionein synthesis could protect from gentamicin nephrotoxicity in suspended proximal tubules of rats. 818 47


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