Sodium-2-mercaptoethanesulfonate (MESNA) and Ifosfamide Nephrotoxicity

Hilgard, P.; Burkert, H.

doi:10.1016/0277-5379(84)90067-1

Cited by 16 publications

(3 citation statements)

References 3 publications

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“…This difference in sensitivity may be due to differences in biotransformation capacity [220]. Since 2-mercaptoethane sulphonate (MESNA) protects rats against nephrotoxicity and carcinogenicity induced by oxidative stress by increasing free thiol groups in kidney [221,222], the potential protective effect of MESNA on renal toxicity and carcinogenicity induced by OTA was examined in a long term rat study [223]. MESNA significantly decreased karyomegalies in kidney of all OTA-treated animals but had no beneficial effect on renal tumour incidence.…”

Section: Carcinogenicitymentioning

confidence: 99%

Ochratoxin A: An overview on toxicity and carcinogenicity in animals and humans

Pfohl‐Leszkowicz¹,

Manderville²

2006

Molecular Nutrition Food Res

896

525

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Ochratoxin A (OTA) is a ubiquitous mycotoxin produced by fungi of improperly stored food products. OTA is nephrotoxic and is suspected of being the main etiological agent responsible for human Balkan endemic nephropathy (BEN) and associated urinary tract tumours. Striking similarities between OTA-induced porcine nephropathy in pigs and BEN in humans are observed. International Agency for Research on Cancer (IARC) has classified OTA as a possible human carcinogen (group 2B). Currently, the mode of carcinogenic action by OTA is unknown. OTA is genotoxic following oxidative metabolism. This activity is thought to play a central role in OTA-mediated carcinogenesis and may be divided into direct (covalent DNA adduction) and indirect (oxidative DNA damage) mechanisms of action. Evidence for a direct mode of genotoxicity has been derived from the sensitive 32P-postlabelling assay. OTA facilitates guanine-specific DNA adducts in vitro and in rat and pig kidney orally dosed, one adduct comigrates with a synthetic carbon (C)-bonded C8-dG OTA adduct standard. In this paper, our current understanding of OTA toxicity and carcinogenicity are reviewed. The available evidence suggests that OTA is a genotoxic carcinogen by induction of oxidative DNA lesions coupled with direct DNA adducts via quinone formation. This mechanism of action should be used to establish acceptable intake levels of OTA from human food sources.

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Section: Carcinogenicitymentioning

confidence: 99%

Ochratoxin A: An overview on toxicity and carcinogenicity in animals and humans

Pfohl‐Leszkowicz¹,

Manderville²

2006

Molecular Nutrition Food Res

896

525

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“…However, even in pa tients on adequate mesna therapy and without cystitis, nephrotoxic effects are detectable. Several cases of severe tubular dysfunction have been reported, in some cases children developed Fanconi syndrome after IF therapy [10][11][12][13][14]. Nephrotoxicity with tubular dysfunc tion is not a typical side effect of CP.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Sodium-Dependent Transport Systems in LLC-PK<sub>1</sub> Cells by Metabolites of Ifosfamide

Mohrmann

Pauli²,

Ritzer³

et al. 1992

Kidney Blood Press Res

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Ifosfamide (IF) is an alkylating cytostatic derived from nitrogen mustard. In addition to its well-known urotoxic effects (hemorrhagic cystitis), several cases of Fanconi syndrome following IF therapy have been reported. No information is available concerning the pathomechanisms of this tubulotoxicity. We used the permanent renal epithelial cell line LLC-PK₁ in order to investigate whether major metabolites of IF (i.e. 4-OH-IF, acrolein and chloracetyldehyde) induce the transport defects most frequently detected after IF therapy in vivo. LLC-PK₁ cells of passages 162-177, grown in plastic culture dishes, were used in a confluent state. Sodium-dependent and independent fluxes of l-[³H]alanine and of D-[³H] glucose were determined by standard techniques. Activities of marker enzymes of apical and basolateral membranes, of mitochondria and of endoplasmic reticulum were determined in cell homogenates. IF itself has no detectable effect on fluxes of /-alanine and D-glucose in LLC-PK, cells. The IF metabolite 4-OOH-IF induces a clear inhibition of sodium-dependent fluxes of both substrates after a 24-hour exposure of cells to 100 µmol/l of 4-OOH-IF. Chloracetaldehyde induces a biphasic response of sodium-dependent fluxes of l-alanine with increased uptake rates at low concentrations ( < 200 µmol/l) and with a short incubation time, while higher concentrations and long exposure of the cells leads to a reduction in sodium coupled transport. Glucose transport is affected in a comparable way, however, in contrast to alanine transport, chloracetaldehyde also stimulates sodium-independent fluxes of glucose. Acrolein is the most toxic substance tested. It severely damages cell monolayers at concentrations beyond 75 µmol/l. Sodium-coupled glucose and alanine transport is inhibited by acrolein at concentrations higher than 50 µmol/l. Sodium-coupled glucose transport is more sensitive to all metabolites tested than alanine transport. While acrolein strongly affects both transport systems, marker enzymes of the apical plasma membrane, i.e. alkaline phosphatase and leucine aminopeptidase, are not significantly inhibited, suggesting a specificity of the toxic effect for the transport proteins. We conclude that LLC-PK₁ cells represent a good model for further investigation of the pathogenesis of Fanconi syndrome after IF therapy. Sodium-dependent transport systems are more sensitive to acrolein than other cell surface proteins.

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“…A well-known side effect of IF is the development of hemorrhagic cystitis which is ascribed to the toxic metabolite acro lein [6,7]. Hemorrhagic cystitis can be pre vented by concomitant application of the uroprotective drug sodium-2-mercaptoethanesulfonate (Mesna) [8,9], Recent reports [10][11][12][13][14] show that even in patients on Mesna therapy and without hemorrhagic cystitis, there is a low but significant percentage of nephrotoxic side effects in children on IF ther apy, ranging from mild tubular dysfunction to severe tubular damage resulting in irrevers ible Fanconi syndrome. As there is little in formation about pathomechanisms and me tabolites involved in tubulotoxicity after IF, we decided to establish an experimental mod el of Fanconi syndrome induced by IF me tabolites.…”

mentioning

confidence: 99%

Effect of Ifosfamide Metabolites on Sodium-Dependent Phosphate Transport in a Model of Proximal Tubular Cells (LLC-PK<sub>1</sub>) in Culture

Mohrmann¹,

Pauli²,

Walkenhorst³

et al. 1993

Kidney Blood Press Res

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Ifosfamide (IF) is an alkylating cytostatic drug with urotoxic (hemorrhagic cystitis) and nephrotoxic side effects. Several cases of Fanconi syndrome in children following therapy with IF were reported. Little information is available concerning the pathomechanisms of transport inhibition by IF. We used a permanent renal epithelial cell line with proximal tubular characteristics (LLC-PK₁) in order to investigate the effects of IF and some of its major metabolites (4-OH-IF, chloracetaldehyde, and acrolein). LLC-PK₁ cells were used in a confluent state. Sodium-dependent and sodium-independent fluxes of ³²PO₄ were determined by standard techniques. Activities of marker enzymes of apical and basolateral membranes, of mitochondria, and of endoplasmic reticulum were determined in cell homogenates. IF induces a moderate stimulation of PO₄ transport. 4-OH-IF also has a stimulatory effect on transport at low concentrations (up to 200 µmol/ l) and with short incubation (2h), while a 24-hour exposure of cells to 100 µmol/l of 4-OH-IF has an inhibitory effect of PO₄ transport. Concentrations of 4-OH-IF which inhibit transport also reduce the activity of Na⁺-K⁺-ATPase. Chloracetaldehyde, like 4-OH-IF, induces a biphasic response of PO₄ transport with stimulation in the low concentration range (up to 75 µmol/l) and inhibition at higher concentrations. Chloracetaldehyde reduces the activity of succinate-cytochrome coxidoreductase, suggesting that a defect in ATP generation might play a role in the pathogenesis of Fanconi syndrome induced by IF. Acrolein strongly damages monolayers and reduces sodium-dependent transport of P0₄ to very low levels at 150 µmol/l. It reduces the activities of both Na⁺-K⁺ ATPase and succinate-cytochrome c oxidoreductase. Acrolein also is the only metabolite with a moderate effect on alkaline phosphatase. We conclude that sodium-dependent transport of PO₄ is highly sensitive to IF metabolites. In addition to direct toxic effects of IF metabolites on transport proteins within the apical plasma membrane, damage to mitochondrial enzymes and to Na⁺-K⁺ ATPase which generates the electrochemical gradients for secondary active PO₄ transport may play an important role in the pathogenesis of Fanconi syndrome induced by IF.

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Sodium-2-mercaptoethanesulfonate (MESNA) and Ifosfamide Nephrotoxicity

Cited by 16 publications

References 3 publications

Ochratoxin A: An overview on toxicity and carcinogenicity in animals and humans

Ochratoxin A: An overview on toxicity and carcinogenicity in animals and humans

Inhibition of Sodium-Dependent Transport Systems in LLC-PK<sub>1</sub> Cells by Metabolites of Ifosfamide

Effect of Ifosfamide Metabolites on Sodium-Dependent Phosphate Transport in a Model of Proximal Tubular Cells (LLC-PK<sub>1</sub>) in Culture

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