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)

The effect of preventive and therapeutical function of Chinese herbs compound prescription Jian-Pi Yi-qi Li-Shui decoction (JPYQLSD) on cisplatin (DDP) and nephrotoxicity of rat. It was carried out that the prescription JPYQLSD had notable result in reducing content of serum urea nitrogen, glucosaminidase, beta 2-microglobulin of the rats (P < 0.05). JPYQLSD also could alleviate inhibition on activity of adenosine triphosphatase (ATP-ase). Pathological examination revealed the protective effect of the JPYQLSD on kidneys of rats. It suggested that JPYQLSD has a good effect on preventive and therapeutical function of Cisplatin (DDP) nephrotoxicity. The mechanism of JPYQLSD was to regulate the energy metabolism of rats.
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PMID:[Effect of preventive and therapeutical function of jian-pi yi-qi li-shui decoction on cisplatin nephrotoxicity in rats]. 133 69

We examined the importance of the Na+, K(+)-ATPase in cisplatin (DDP) accumulation in 2008 human ovarian carcinoma cells and describe changes in the Na+, K(+)-ATPase in DDP-resistant cells with DDP accumulation defects. Approximately 50% of DDP accumulation was inhibitable by ouabain. DDP accumulation into 2008 cells could be maximally inhibited when cells were preincubated with ouabain for 1 h prior to DDP exposure. The half-maximal inhibition was obtained with 0.13 microM ouabain. Similar inhibition of DDP accumulation was obtained when the Na+, K(+)-ATPase was blocked by ATP depletion or by incubating cells in K(+)-free medium. This same percentage of DDP accumulation was Na+ dependent and varied directly with Na+ concentration. These effects on DDP accumulation could be detected as early as 1 min after the imposition of 0-trans conditions, strongly suggesting that the inhibition was due to modulation of a drug influx step. The Na+, K(+)-ATPase in 2008/DDP cells had a similar KD for ouabain binding and 36% less Na+, K(+)-ATPase molecules/mg of protein than 2008 cells. 2008/DDP cells 2.3 +/- 0.2 (SE, n = 3) fold cross-resistant to ouabain in a continuous exposure clonogenic assay. Despite these changes in the Na+, K(+)-ATPase, the net basal Na+, K(+)-ATPase activity was the same in sensitive and DDP-resistant cells as determined by ouabain-inhibitable 86Rb+ influx. The basal Na+ levels were also similar in the sensitive and resistant cells. These data suggest that DDP accumulation is partially Na+ dependent and that, therefore, the Na+, K(+)-ATPase which maintains the Na+ gradient may play an important role in determining how much DDP enters cells. Whether there is a causal link between the changes in the Na+, K+-ATPase in DDP-resistant cells and their DDP accumulation defect is not yet known.
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PMID:Role of the Na+, K(+)-adenosine triphosphatase in the accumulation of cis-diamminedichloroplatinum(II) in human ovarian carcinoma cells. 164 42

Oxygen consumption (QO2) and net K+ transport were studied in rabbit proximal tubule suspensions to define the early effects of cisplatin on proximal tubule function. Cisplatin caused dose-dependent inhibition of QO2, which was delayed in onset. The concentration of cisplatin required for inhibition decreased as the duration of exposure was increased [40-min exposure, threshold concentration of 10(-4) M, inhibitor constant (Ki) of 10(-3) M; 4-h exposure, threshold concentration of 3 X 10(-5) M, Ki of 10(-4) M]. Both ouabain-sensitive and ouabain-insensitive QO2 were reduced, indicating inhibition of all adenosinetriphosphatases, including Na(+)- K(+)-ATPase activity. There was a parallel fall in ouabain-sensitive net K+ transport and cytosolic K+ content, confirming the latter observation. Na(+)-K(+)-ATPase activity was unchanged in cell membranes prepared by hypotonic lysis from cisplatin-treated tubules, indicating an indirect cytosol-dependent mechanism of enzyme inhibition. Nystatin-stimulated QO2 was reduced in cisplatin-treated tubules, excluding inhibition of Na+ entry as the mechanism of injury and suggesting mitochondrial injury. The latter was confirmed by measurement of carbonylcyanide-m-chlorophenylhydrazone (CCCP)-uncoupled QO2 in intact cells and ADP-stimulated (state 3) QO2 in digitonin-permeabilized tubules. Furthermore, by maximally stimulating mitochondrial respiration with CCCP and nystatin, it was possible to demonstrate mitochondrial injury at a time when basal QO2 and K+ transport were apparently normal. These data suggest that mitochondrial injury is a central event in cisplatin toxicity to the proximal tubule.
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PMID:Mitochondrial injury: an early event in cisplatin toxicity to renal proximal tubules. 215 14

Cisplatin and chloroplatinic acid were examined for in vitro inhibition of human renal microsomal adenosine triphosphatases activated by Na+ + K+ + Mg2+, Mg2+, and Ca2+. The concentrations of cisplatin to inhibit 50% of activity (I50) were approximately 7 X 10(-4) M for all enzymes studied; I50s of chloroplatinic acid were on the order of 10(-5) M for Na+ + K+ + Mg2+ ATPase and Ca2+ ATPase and 10(-7) M for Mg2+ ATPase in the presence of Na+ + K+ + ouabain. Inhibition of Na+ + K+ + Mg2+ ATPase by cisplatin or chloroplatinic acid was reversible and was not altered by varying Na+, K+, or Mg2+ concentrations; ATP or MgATP increased inhibition by cisplatin but not by chloroplatinic acid; acidic pH of 6.8 lowered inhibition by chloroplatinic acid but not by cisplatin. Cysteine, glutathione (-SH reagents), and ascorbic acid greatly reduced inhibition of all enzymes studied by chloroplatinic acid; in the case of cisplatin, -SH reagents had only a minimal protective effect but ascorbic acid somewhat increased inhibition. Methionine greatly increased inhibition by cisplatin but provided minimal protection in the case of chloroplatinic acid. In view of the hypothesis that inhibition of renal Na+ + K+ ATPase may be associated with tubular damage, the inhibition of Na+ + K+ ATPase may be relevant to the mechanism of platinum toxicity.
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PMID:Characteristics of inhibition of human renal adenosine triphosphatases by cisplatin and chloroplatinic acid. 614 41

This study was performed to determine the effect of cisplatin (cis-diamminedichloroplatinum II) on renal function in rabbits. Injection of a single i.p. dose of 4 mg/kg cisplatin caused an increase in fractional excretion of Na+ and K+ and a decrease in urine osmolality (Uosm), free-water reabsorption, (TcH2O), and urine to plasma creatinine ratio (U/Pcr). Urine flow was decreased following cisplatin treatment, which was accompanied by marked reduction in GFR. Cisplatin induced glucosuria, phosphaturia, and aminoaciduria. These results suggest that cisplatin results in impaired proximal tubular reabsorptive function and the renal concentrating defect. Cisplatin treatment impaired the accumulation of PAH and TEA and ouabain-sensitive oxygen consumption in renal cortical slices. Na(+)-K(+)-ATPase activity in renal cortical microsomes and basolateral membrane vesicles was significantly depressed in cisplatin-treated animals. Cisplatin treatment did not affect the Na(+)-dependent uptake of glucose and L-glutamate by brush-border membrane vesicles (BBMV), but caused a significant decrease in Na(+)-dependent succinate and H(+)-dependent TEA uptake. Morphological observations showed that cisplatin caused a focal loss of the microvillus brush border. These results suggest that (1) cisplatin induces oliguric acute renal failure in rabbits and (2) glucosuria induced by cisplatin was not due to a direct impairment of glucose transporter in brush-border membranes but due to an inhibition of Na(+)-pump activity and a decrease in area for active glucose reabsorption in the proximal tubule.
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PMID:Effect of cisplatin on renal function in rabbits: mechanism of reduced glucose reabsorption. 783 66

RecB and RecA proteins play key roles in the process of DNA recombination in Escherichia coli and both possess DNA unwinding activities which can displace short regions of duplex DNA in an ATP-dependent manner in vitro. We have examined the effect of the most abundant DNA adduct caused by the chemotherapeutic agent cis-diamminedichloroplatinum(II) on those activities. For this purpose, we have constructed a partially duplex synthetic oligonucleotide containing the intrastrand d(GpG) crosslink positioned at a specific site. We report here that both the DNA strand separating and DNA-dependent ATPase activities of the RecB protein are inhibited by the d(GpG) cis-DDP adduct. In contrast, neither the unwinding nor the ATPase activities of RecA protein appear to be perturbed by this lesion.
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PMID:Effects of a single intrastrand d(GpG) platinum adduct on the strand separating activity of the Escherichia coli proteins RecB and RecA. 822 77

Calf DNA helicase E (hel E) is a moderately processive, 3' to 5' helicase, active on nicked DNA, that we have proposed to have a role in DNA repair (Turchi, J. J., Murante, R. S., and Bambara, R. A. (1992) Nucleic Acids Res. 20, 6075-6080). Here we have examined its activity on a series of cis-diamminedichloroplatinum (II) (cis-DDP)-modified DNA substrates. Hel E was capable of efficiently displacing a primer strand containing, in an internal position, a cis-DDP-modified dGG. In a two-primer model system, calf DNA polymerase epsilon could successfully extend an upstream primer through a cis-DDP-modified down-stream primer, to the end of the complementary template strand, in a reaction dependent on hel E. However, the translocation of hel E was blocked by cis-DDP modification of the template strand. Primer displacement was completely prevented if the modified site was located just upstream of the primer. The DNA-dependent ATPase activity of helicase E was also reduced by cis-DDP modification of the template DNA. Substrate competition experiments indicated that cis-DDP-modified DNA templates did not sequester hel E. Substrate titration experiments suggested that there is a short delay without ATP hydrolysis before dissociation of helicase E from cis-DDP-modified template sites. Interestingly, hel E could displace a primer if the cis-DDP modification was on the template within the annealed region. Possible explanations for this are discussed. Taken together, these results are consistent with the proposal that hel E participates in DNA repair by displacing segments of damaged DNA.
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PMID:Activity of calf thymus DNA helicase E on cis-diamminedichloroplatinum (II)-damaged DNA. 825 8

Cisplatin (CP) nephrotoxicity in vivo is characterized by proximal tubule (PT) and collecting duct dysfunction. We reported previously that mitochondrial injury is an important early event in CP toxicity to PT cells and precedes inhibition of Na+,K(+)-ATPase activity and loss of cell K+. In the present study, we monitored oxygen consumption (QO2) and net K+ fluxes in intact inner medullary collecting duct (IMCD) and PT cells in vitro, using O2- and K(+)-sensitive electrodes, to determine if CP has similar effects on IMCD cells. Short-term exposure of IMCD cells to CP resulted in inhibition of spontaneous, ouabain-sensitive and ouabain-oversensitive QO2, but to a lesser degree than in PT. Ouabain-sensitive K+ transport and cell K+ content were also reduced in intact IMCD cells in this setting, confirming inhibition of Na+,K(+)-ATPase activity. In contrast, Na+,K(+)-ATPase activity measured in IMCD cell lysates was not altered. These results suggested that CP inhibited Na+,K(+)-ATPase activity in intact IMCD cells indirectly either by blocking Na+ entry or by inhibiting mitochondrial oxidative phosphorylation. Nystatin (Na+ ionophore) and carbonyl cyanide m-chlorophenylhydrazone (CCCP, uncoupler of oxidative phosphorylation) were used to distinguish between these possibilities. Nystatin-stimulated and CCCP-uncoupled QO2 were reduced in CP-treated IMCD cells by 34 +/- 10% and 25 +/- 5%, respectively, indicating mitochondrial injury. Again, the effects of CP on nystatin-stimulated and CCCP-uncoupled QO2 in IMCD cells were significantly less dramatic than in PT cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Differential actions of cisplatin on renal proximal tubule and inner medullary collecting duct cells. 838 66

Cisplatin is the most active anticancer agent for lung cancer. It has been reported that intracellular accumulation of cisplatin is important in determining resistance to cisplatin, which may be modulated by Na+, K(+)-ATPase activity. On the other hand, it is well-known that sorbitol, a metabolite of glucose mediated by aldose reductase, reduces Na+, K(+)-ATPase in diabetic neuropathy. In this study, the effect of exogenous sorbitol on Na+, K(+)-ATPase activity and sensitivity to cisplatin was evaluated using human non-small-cell lung cancer (NSCLC) cell lines. In the NSCLC cell lines, EBC-1, PC-3, and RERF-LC-MS the cytotoxicities of cisplatin were impaired by exposure to sorbitol in these cell lines. Na+, K(+)-ATPase was inactivated and intracellular accumulation of cisplatin was decreased by the exposure. These results suggest that accumulation of sorbitol may induce resistance to cisplatin in NSCLC cells, and diabetes poorly controlled may be one of the determinants of the antitumor effect of cisplatin in NSCLC.
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PMID:Exposure to sorbitol induces resistance to cisplatin in human non-small-cell lung cancer cell lines. 941 70

Na+,K+-ATPase (EC 3.6.1.37) is assumed to be involved in the transport of cisplatin [cis-diamminedichloroplatinum(II)] into cells and to act as a modulator of 5-fluorouracil (5-FU) in combination therapy of cisplatin and 5-FU. Whereas inhibition of Na+,K+-ATPase activity by cisplatin is expected to have effects on both anti-cancer therapy and nephrotoxicity, the inhibition mechanism remains to be elucidated. We studied the inhibition of Na+,K+-ATPase activity by cisplatin using an enzyme partially purified from Ca9-22 cells derived from a human squamous cell carcinoma of the gingiva. Cisplatin inhibited the Na+,K+-dependent ATP hydrolysis activity, and this inhibition depended on both the concentration of cisplatin and the preincubation time with cisplatin. The time-dependent inhibition was thought to be caused by a slow change of cisplatin from the inactive to the active form. We further tested the effect of cisplatin on the partial reactions of the enzyme, Na+-dependent ATP hydrolysis and K+-dependent pnitrophenylphosphate hydrolysis activities to determine which step in the reaction sequence of Na+,K+-ATPase was inhibited. Cisplatin inhibited both activities depending on its concentration and the preincubation time, whereas the Na+-dependent ATP hydrolysis activity was inhibited even at lower concentrations. Formation of a phosphointermediate of Na+,K+-ATPase was also inhibited by cisplatin depending on the concentration and preincubation time. Cisplatin (500 microM) and 8-fold higher concentration of 2-mercaptoethanol (2-ME; 4 mM) prevented inactivation of the enzyme by cisplatin, and the Na+,K+-ATPase activity inhibited by pretreatment with cisplatin was also recovered almost completely by 2-ME. These results suggest that the active form of cisplatin inhibits the Na+,K+-ATPase activity by inhibiting the formation of a phosphointermediate of the enzyme and that the inhibition by cisplatin is arrested by an addition of thiol group.
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PMID:Inhibition of Na+,K+-ATPase by cisplatin and its recovery by 2-mercaptoethanol in human squamous cell carcinoma cells. 1021 51


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