Ifosfamide-Induced Nephrotoxicity: Mechanism and Prevention

Nissim, Itzhak; Horyn, Oksana; Daikhin, Yevgeny; Nissim, Ilana; Luhovyy, Bohdan L.; Phillips, Peter C.B.; Yudkoff, Marc

doi:10.1158/0008-5472.can-06-1043

Cited by 82 publications

(73 citation statements)

References 45 publications

(82 reference statements)

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“…A set of separate experiments was performed similarly but using 15 15 N amino acids were measured by GC-MS as described in previous reports (11,13).…”

Section: C]glucose-batches Of 1000 Cultured Islets From Sur1mentioning

confidence: 99%

“…For measurement of the 13 C enrichment in amino acids, samples were prepared as previously described (14,15). Briefly, an aliquot of islet perchloric acid extract was purified by passage on an AG-1 (Cl Ϫ , 100 -200 mesh; 0.5 ϫ 2.5 cm) or AG-50 (H ϩ , 100 -200 mesh) column and then converted into the t-butyldimethylsilyl derivatives.…”

Section: C]glucose-batches Of 1000 Cultured Islets From Sur1mentioning

confidence: 99%

“…The latter was transferred into autosampler tubes for analysis. Isotopic enrichment in 13 CO 2 was determined by an isotope ratio mass spectrometer (Thermoquest Finnigan Delta Plus) using the m/z 44/45 ratio (14,15).…”

Section: C]glucose-batches Of 1000 Cultured Islets From Sur1mentioning

confidence: 99%

“…Calculations and Statistical Analyses-13 C enrichment is expressed by molar percent enrichment, which is the mol fraction percent of analyte containing 13 C atoms above natural abundance (14,15). The production of 13 C-labeled mass isotopomer was calculated by the product of (molar percent enrichment)/100 times concentration (nmol/1000 islets) and is expressed as nmol of 13 C metabolite/1000 islets.…”

Section: C]glucose-batches Of 1000 Cultured Islets From Sur1mentioning

confidence: 99%

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Elimination of KATP Channels in Mouse Islets Results in Elevated [U-13C]Glucose Metabolism, Glutaminolysis, and Pyruvate Cycling but a Decreased γ-Aminobutyric Acid Shunt

Nissim

Chen

et al. 2008

Journal of Biological Chemistry

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Pancreatic beta cells are hyper-responsive to amino acids but have decreased glucose sensitivity after deletion of the sulfonylurea receptor 1 (SUR1) both in man and mouse. It was hypothesized that these defects are the consequence of impaired integration of amino acid, glucose, and energy metabolism in beta cells. We used gas chromatography-mass spectrometry methodology to study intermediary metabolism of SUR1 knock-out (SUR1 ؊/؊ ) and control mouse islets with D-[U-13 C]glucose as substrate and related the results to insulin secretion. The levels and isotope labeling of alanine, aspartate, glutamate, glutamine, and ␥-aminobutyric acid (GABA) served as indicators of intermediary metabolism. We found that the GABA shunt of SUR1 ؊/؊ islets is blocked by about 75% and showed that this defect is due to decreased glutamate decarboxylase synthesis, probably caused by elevated free intracellular calcium. Glutaminolysis stimulated by the leucine analogue D,L-␤-2-amino-2-norbornane-carboxylic acid was, however, enhanced in SUR1 ؊/؊ and glyburide-treated SUR1 ؉/؉ islets. Glucose oxidation and pyruvate cycling was increased in SUR1 ؊/؊ islets at low glucose but was the same as in controls at high glucose. Malic enzyme isoforms 1, 2, and 3, involved in pyruvate cycling, were all expressed in islets. High glucose lowered aspartate and stimulated glutamine synthesis similarly in controls and SUR1 ؊/؊ islets. The data suggest that the interruption of the GABA shunt and the lack of glucose regulation of pyruvate cycling may cause the glucose insensitivity of the SUR1 ؊/؊ islets but that enhanced basal pyruvate cycling, lowered GABA shunt flux, and enhanced glutaminolytic capacity may sensitize the beta cells to amino acid stimulation.The pancreatic beta cells function as the predominant sensors and regulators of glucose, amino acid, and fatty acid levels of the mammalian organism, including man, by adjusting the minute to minute rate of insulin secretion such that these fuels are maintained at physiologically optimal blood concentrations under all nutritional conditions including feeding and fasting. This process of fuel-sensing and stimulation of insulin secretion requires that the various stimuli are transported into the beta cells and are metabolized to generate coupling factors that trigger and sustain the secretion of the hormone from large stores of insulin granules (1-4). The diverse specific pathways that allow access to metabolism for glucose, amino acids, and fatty acids converge to a complex network of intermediary metabolism represented by the citric acid cycle, a considerable variety of metabolite and cofactor shuttles including the GABA 2 shunt, and the processes of electron transport and oxidative phosphorylation, to mention just a few outstanding features of the biochemical maze of the beta cell.In the present study we have used uniformly labeled D-[13 C]glucose and GC-MS methods to explore the role of intermediary metabolism of pancreatic islets isolated from normal and sulfonylurea receptor 1 (SUR1) knock-out...

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“…A set of separate experiments was performed similarly but using 15 15 N amino acids were measured by GC-MS as described in previous reports (11,13).…”

Section: C]glucose-batches Of 1000 Cultured Islets From Sur1mentioning

confidence: 99%

Section: C]glucose-batches Of 1000 Cultured Islets From Sur1mentioning

confidence: 99%

Section: C]glucose-batches Of 1000 Cultured Islets From Sur1mentioning

confidence: 99%

Section: C]glucose-batches Of 1000 Cultured Islets From Sur1mentioning

confidence: 99%

See 2 more Smart Citations

Elimination of KATP Channels in Mouse Islets Results in Elevated [U-13C]Glucose Metabolism, Glutaminolysis, and Pyruvate Cycling but a Decreased γ-Aminobutyric Acid Shunt

Nissim

Chen

et al. 2008

Journal of Biological Chemistry

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“…The reactive toxic metabolite Chloroacetaldehyde (CAA), which is produced by the side-chain oxidation of IFO in renal tubular cells (Woodland et al, 2000), is believed to cause the nephrotoxic effect (Springate et al, 1999;Aleska et al, 2005) through inducing oxidative stress (Sener et al, 2004;Knouzy et al, 2010). Nissim et al (2006) hypothesized that the CAA-induced dysfunction of mitochondrial oxidative phosphorylation in renal proximal tubules impairs energy production, thereby resulting in multiple metabolic abnormalities and cellular damage. Generally, drugs in developing countries may not always get perfect storing facilities, though facing many unfavorable conditions such as storing in high temperature degrees.…”

Section: Introductionmentioning

confidence: 99%

Effect of Storing Temperature on Hepatotoxicity and Nephrotoxicity of Ifosfamide in Female Rat

Aziz¹

2012

OnLine Journal of Biological Sciences

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Problem statement: Ifosfamide (IFO) is a cytotoxic alkylating drug used for the treatment of a variety of cancers, although it has been found to induce certain hematological, hepatotoxic and nephrotoxic side effects. This drug is widely used in developing country, especially Iraq, but without caring too much to the storing temperature due to low drug maintaining facilities. The present work was achieved to investigate the effect of different temperature degrees on the toxicity of IFO on liver and kidney of female rats. Approach: Ifosfamide (60 mg Kg −1 b.wt) stored at different temperature degrees (4, 10 and 25°C) was given to female rats to detect the effect of temperature degrees on hepatotoxicity and nephrotoxicity of this chemotherapeutic drug. A modified technique was used for demonstration the dying kidney cells. Results: All IFO treated rats showed Fanconi syndrome such as increase of serum creatinine, phosphorus, ALT and AST and decrease of glucose as well as an increase in serum Malondialdehyde (MDA) level. Ifosfamide was still maintained its antimitotic action in all the treated groups as revealed by examining the bone marrow smears. The biochemical estimation of ALT, AST and MDA showed significant temperature dependent increase in the toxicity of liver and kidney by this drug. The histopathological alteration in these two organs were come supportive to the above biochemical results. The liver of the rats exposed to IFO stored at 25°C showed higher liver steatosis, hemorrhage and more degeneration of hepatocytes. Similarly, more hemorrhage, degeneration of kidney tubule cells and lymphocytes infiltration in kidney were observed in the 25°C group in comparison to the other groups. A successful modified technique for staining thick plastic sections was employed revealing a specific color for the dying kidney cells. Conclusion: Although it can maintain its antimitotic property, IFO caused more severe hepatotoxic and nephrotoxic side effects if it is stored at temperature degree higher than 4°C.

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Ifosfamide metabolite chloroacetaldehyde inhibits cell proliferation and glucose metabolism without decreasing cellular ATP content in human breast cancer cells MCF‐7

Knouzy

Dubourg

Baverel

et al. 2009

J of Applied Toxicology

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Chloroacetaldehyde (CAA), a product of hepatic metabolism of the widely used anticancer drug ifosfamide (IFO), has been reported to decrease cancer cell proliferation. The basis of this effect is not completely known but has been attributed to a drop of cellular ATP content. Given the importance of glucose metabolism and of the 'Warburg effect' in cancer cells, we examined in the present study the ability of CAA to inhibit cancer cell proliferation by altering the glycolytic pathway. Cell proliferation, ATP content, glucose transport and metabolism as well as the activities of the main enzymes of glycolysis were determined in human breast cancer cells MCF-7 in the presence of various CAA concentrations (5-50 microm). Our results show that low CAA concentrations inhibited cell proliferation in a concentration-dependent manner. This inhibition was explained by a decrease in glucose utilization. Cellular ATP content was not reduced but even increased with 25 microm CAA. The inhibition of glucose metabolism was mainly explained by the decrease in glucose transport and hexokinase activity. The activity of glyceraldehyde-3-phosphate dehydrogenase, but not that of phosphofructokinase, was also inhibited. Glycolysis inhibition by CAA was effective in decreasing the proliferation of MCF-7 cells. Interestingly, this decrease was not due to ATP depletion; rather, it was linked to a drop of biosynthetic precursors from glycolytic intermediates. This CAA-induced inhibition of cell proliferation suggests that it might play a role in the antitumor activity of IFO.

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Ifosfamide-Induced Nephrotoxicity: Mechanism and Prevention

Cited by 82 publications

References 45 publications

Elimination of KATP Channels in Mouse Islets Results in Elevated [U-13C]Glucose Metabolism, Glutaminolysis, and Pyruvate Cycling but a Decreased γ-Aminobutyric Acid Shunt

Elimination of KATP Channels in Mouse Islets Results in Elevated [U-13C]Glucose Metabolism, Glutaminolysis, and Pyruvate Cycling but a Decreased γ-Aminobutyric Acid Shunt

Effect of Storing Temperature on Hepatotoxicity and Nephrotoxicity of Ifosfamide in Female Rat

Ifosfamide metabolite chloroacetaldehyde inhibits cell proliferation and glucose metabolism without decreasing cellular ATP content in human breast cancer cells MCF‐7

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