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Michael Gekle - One of the best experts on this subject based on the ideXlab platform.
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The Nephrotoxic Ifosfamide-Metabolite Chloroacetaldehyde Interferes with Renal Extracellular Matrix Homeostasis
Karger Publishers, 2014Co-Authors: Andreas Benesic, Gerald Schwerdt, Isabell Hennemeier, Christoph Sauvant, Sigrid Mildenberger, Michael GekleAbstract:Background/Aims: Chronic renal proximal tubule dysfunction after therapy with the antineoplastic agent ifosfamide (IFO) is often attributed to the metabolite Chloroacetaldehyde (CAA). Chronic IFO-nephropathy is reported to result in tubulointerstitial fibrosis and inflammation. Methods: To elucidate possible effects of CAA on extracellular matrix homeostasis, we investigated the action of CAA on markers of extracellular matrix (ECM) homeostasis in human proximal tubule cells (RPTEC) by use of direct ELISA for extracellular collagens and gelatin zymography. Results: An increase in type III collagen and a decrease in type IV collagen abundance in the media of RPTEC could be observed after exposure to CAA in clinically relevant concentrations. CAA increased intracellular type III and decreased intracellular type IV collagen. MMP-2 activity was decreased but MMP-9 activity unchanged. The enhanced CAA-induced collagen III formation could be attenuated by the intracellular Ca2+-chelator BAPTA-AM, the PKA-antagonist H-89 and by extracellular acidification. CAA-induced collagen III abundance was enhanced by db-cAMP and IBMX and by protein overload. Conclusions: CAA exerts profibrotic effects on RPTEC dependent on Ca2+ and cAMP/PKA-signaling. These effects are enhanced by additional protein burden and attenuated by acidification
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the nephrotoxic ifosfamide metabolite Chloroacetaldehyde interferes with renal extracellular matrix homeostasis
Cellular Physiology and Biochemistry, 2014Co-Authors: Andreas Benesic, Gerald Schwerdt, Isabell Hennemeier, Christoph Sauvant, Sigrid Mildenberger, Michael GekleAbstract:BACKGROUND/AIMS Chronic renal proximal tubule dysfunction after therapy with the antineoplastic agent ifosfamide (IFO) is often attributed to the metabolite Chloroacetaldehyde (CAA). Chronic IFO-nephropathy is reported to result in tubulointerstitial fibrosis and inflammation. METHODS To elucidate possible effects of CAA on extracellular matrix homeostasis, we investigated the action of CAA on markers of extracellular matrix (ECM) homeostasis in human proximal tubule cells (RPTEC) by use of direct ELISA for extracellular collagens and gelatin zymography. RESULTS An increase in type III collagen and a decrease in type IV collagen abundance in the media of RPTEC could be observed after exposure to CAA in clinically relevant concentrations. CAA increased intracellular type III and decreased intracellular type IV collagen. MMP-2 activity was decreased but MMP-9 activity unchanged. The enhanced CAA-induced collagen III formation could be attenuated by the intracellular Ca(2+)-chelator BAPTA-AM, the PKA-antagonist H-89 and by extracellular acidification. CAA-induced collagen III abundance was enhanced by db-cAMP and IBMX and by protein overload. CONCLUSIONS CAA exerts profibrotic effects on RPTEC dependent on Ca(2+) and cAMP/PKA-signaling. These effects are enhanced by additional protein burden and attenuated by acidification. © 2014 S. Karger AG, Basel.
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Chloroacetaldehyde and acrolein induced death of human proximal tubule cells
Pediatric Nephrology, 2006Co-Authors: Gerald Schwerdt, Nader Gordjani, Andreas Benesic, Ruth Freudinger, Brigitte Wollny, Antje Kirchhoff, Michael GekleAbstract:Ifosfamide (ifo) is a commonly used drug in chemotherapy. It is metabolized to acrolein (acro) and Chloroacetaldehyde (CAA), which are thought to be responsible for renal side effects. We studied the effects of ifo and cyclophosphamide (cyclo) as well as their metabolites, acro and CAA, on cellular protein content, necrosis, apoptosis and cytosolic calcium concentration using a human proximal tubule cell line. The protein content decreased during acro or CAA administration (15 to 300 µmol/l), but not during ifo or cyclo exposure over a time period of up to 72 h. Mild apoptosis was induced only by high acro (150, 300 µmol/l) and low CAA concentrations (15, 75 µmol/l) and only in a narrow time window (24 h). Necrosis was increased after exposure to acro or CAA at all concentrations. CAA was more potent than acro. Ifo and cyclo did not induce necrosis or apoptosis. Glutathione abolished CAA-induced cell death. Cytosolic calcium concentrations increased after acro or CAA administration and showed an oscillating pattern. Cytosolic Ca2+ chelation did not prevent necrosis. We conclude that neither ifo nor cyclo induce cell damage, but that their metabolites acro and CAA induce cell death. This cell death occurs mainly by necrosis and not by apoptosis.
Darren Rhodes - One of the best experts on this subject based on the ideXlab platform.
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Ethenoadenine Precursor 7,8-dihydro-7-hydroxy-imidazo[2,1-i]purine TS
2015Co-Authors: Darren RhodesAbstract:The reaction of Chloroacetaldehyde with adenine to form ethenoadenine has been modelled: this is a transition state structure at the 6-31G(d) level of theory using the wB97X-D functional. When Chloroacetaldehyde reacts with adenine to form ethenoadenine the reaction can proceed by one of two routes dependent upon the orientation of the Chloroacetaldehyde molecule with the adenine molecule. This model is based upon an orientation which would form the intermediate 7,8-dihydro-7-hydroxy-imidazo[2,1-i]purine.
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Ethenoadenine Precursor 7,8-dihydro-7-hydroxy-imidazo[2,1-i]purine IRC
2015Co-Authors: Darren RhodesAbstract:The reaction of Chloroacetaldehyde with adenine to form ethenoadenine has been modelled: this is an intrinsic reaction coordinate for the dehydration reaction at the 6-31G(d) level of theory using the wB97X-D functional. When Chloroacetaldehyde reacts with adenine to form ethenoadenine the reaction can proceed by one of two routes dependent upon the orientation of the Chloroacetaldehyde molecule with the adenine molecule. This model is based upon an orientation which would form the intermediate 7,8-dihydro-7-hydroxy-imidazo[2,1-i]purine.
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Ethenoadenine Precursor 7,8-dihydro-8-hydroxy-imidazo[2,1-i]purine dehydration
2015Co-Authors: Darren RhodesAbstract:The reaction of Chloroacetaldehyde with adenine to form ethenoadenine has been modelled: this is an intrinsic reaction coordinate at the 6-31G(d) level of theory using the wB97X-D functional in water. When Chloroacetaldehyde reacts with adenine to form ethenoadenine the reaction can proceed by one of two routes dependent upon the orientation of the Chloroacetaldehyde molecule with the adenine molecule. This model is based upon an orientation which would form the intermediate 7,8-dihydro-8-hydroxy-imidazo[2,1-i]purine. This model also uses an explicit water molecule in the elimination reaction.
Weinong Zhang - One of the best experts on this subject based on the ideXlab platform.
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a novel approach of periodate oxidation coupled with hplc fld for the quantitative determination of 3 chloro 1 2 propanediol in water and vegetable oil
Journal of Agricultural and Food Chemistry, 2013Co-Authors: Peng Cheng, Mingli Guo, Weinong ZhangAbstract:A novel approach of periodate oxidation coupled with high-performance liquid chromatography (HPLC)–fluorescence detection (FLD) for the quantitative determination of 3-chloro-1,2-propanediol (3-MCPD) has been established. The essence of this approach lies in the production of Chloroacetaldehyde by the oxidization cleavage of 3-MCPD with sodium periodate and the HPLC analysis of Chloroacetaldehyde monitored by an FLD detector after fluorescence derivatization with adenine. The experimental parameters relating to the efficiency of the derivative reaction such as concentration of adenine, Chloroacetaldehyde reaction temperature, and time were studied. Under the optimized conditions, the proposed method can provide high sensitivity, good linearity (r2 = 0.999), and repeatability (percent relative standard deviations between 2.57% and 3.44%), the limits of detection and quantification were 0.36 and 1.20 ng/mL, respectively, and the recoveries obtained for water samples were in the range 93.39–97.39%. This meth...
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A Novel Approach of Periodate Oxidation Coupled with HPLC-FLD for the Quantitative Determination of 3‑Chloro-1,2-propanediol in Water and Vegetable Oil
2013Co-Authors: Peng Cheng, Mingli Guo, Weinong ZhangAbstract:A novel approach of periodate oxidation coupled with high-performance liquid chromatography (HPLC)–fluorescence detection (FLD) for the quantitative determination of 3-chloro-1,2-propanediol (3-MCPD) has been established. The essence of this approach lies in the production of Chloroacetaldehyde by the oxidization cleavage of 3-MCPD with sodium periodate and the HPLC analysis of Chloroacetaldehyde monitored by an FLD detector after fluorescence derivatization with adenine. The experimental parameters relating to the efficiency of the derivative reaction such as concentration of adenine, Chloroacetaldehyde reaction temperature, and time were studied. Under the optimized conditions, the proposed method can provide high sensitivity, good linearity (r2 = 0.999), and repeatability (percent relative standard deviations between 2.57% and 3.44%), the limits of detection and quantification were 0.36 and 1.20 ng/mL, respectively, and the recoveries obtained for water samples were in the range 93.39–97.39%. This method has been successfully applied to the analysis of real water samples. Also this method has been successfully used for the analysis of vegetable oil samples after pretreatment with liquid–liquid extraction; the recoveries obtained by a spiking experiment with soybean oil ranged from 96.27% to 102.42%. In comparison with gas chromatography or gas chromatography–mass spectrometry, the proposed method can provide the advantages of simple instrumental requirement, easy operation, low cost, and high efficiency, thus making this approach another good choice for the sensitive determination of 3-MCPD
Stoeckli-evans Helen - One of the best experts on this subject based on the ideXlab platform.
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Rac-(2R*,3R*)- S -Ethyl-4-Chloro-3-Hydroxy-2-Phenylbuthanethioate and Rac-(2R*,3R*)- S -Ethyl-2-Phenyl-3-(tosyloxy)buthanethioate: Dichotomy of the Stereoselectivity of the Mukaiyama Reaction
2018Co-Authors: Vallat Oliver, Buciumas Ana-maria, Neier Reinhard, Stoeckli-evans HelenAbstract:The title compounds, rac-(2R*,3R*)-S-ethyl-4-chloro-3-hydroxy-2-phenylbuthanethioate (I) and rac-(2R*,3R*)-S-ethyl-2-phenyl-3-(tosyloxy)buthanethioate (III), are both composed of a S-ethyl 2-phenylbutanethioate moiety but have different geometries. Compound I is substituted in the 3 and 4 positions by a hydroxyl group and a chlorine atom, respectively. In compound III the hydroxyl group in the 3 position of rac-(2R*,3R*)-S-ethyl-3-hydroxy-2-phenylbuthanethioate (II), has been tosylated in order to obtain suitable crystals for X-ray analysis. In compound I the phenyl substituent and the hydroxyl group have a syn arrangement, whereas in the tosylate derivative of II, i.e., compound III, they have an anti arrangement. In the crystal structure of I centrosymmetric hydrogen bonded dimers are formed via O-H···O hydrogen bonds, involving the hydroxyl group and the carbonyl O-atom. In the crystal structure of III symmetry related molecules are connect via a weak C-H···O intermolecular interaction, involving a tosylate O-atom and a phenyl H-atom, so forming zigzag chains propagating in the c direction. The compounds were prepared by the Mukaiyama crossed aldol reaction between the silyl enol ether of S-ethyl 2-phenylethanethioate and simple aldehydes, like 2-Chloroacetaldehyde (for I) and acetaldehyde (for II). The syn/anti stereo descriptors clearly indicate that the stereoselectivity of the Mukaiyama aldol reaction has switched from a syn selective process for the reaction using 2-Chloroacetaldehyde to an anti selective process for the reaction with acetaldehyde. In both compounds the relative stereochemistry at the newly created chiral centers, positions 2 and 3, is R/R. Graphical Abstract: The compounds, rac-(2R*,3R*)-S-ethyl-4-chloro-3-hydroxy-2-phenylbuthanethioate (I) and rac-(2R*,3R*)-S-ethyl-3-hydroxy-2-phenylbuthanethioate (II), were prepared by the Mukaiyama crossed aldol reaction between the silyl enol ether of S-ethyl 2-phenylethanethioate and simple aldehydes, like 2-Chloroacetaldehyde (for I) and acetaldehyde (for II). The stereoselectivity of the Mukaiyama aldol reaction was shown to have switched from a syn selective process for the reaction using 2-Chloroacetaldehyde to an anti selective process for the reaction with acetaldehyd
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Rac-(2R*,3R*)-S-Ethyl-4-Chloro-3-Hydroxy-2-Phenylbuthanethioate and Rac-(2R*,3R*)-S-Ethyl-2-Phenyl-3-(tosyloxy)buthanethioate: Dichotomy of the Stereoselectivity of the Mukaiyama Reaction
2010Co-Authors: Vallat Oliver, Buciumas Ana-maria, Neier Reinhard, Stoeckli-evans HelenAbstract:The title compounds, rac-(2R*,3R*)-S-ethyl-4-chloro-3-hydroxy-2-phenylbuthanethioate (I) and rac-(2R*,3R*)-S-ethyl-2-phenyl-3-(tosyloxy)buthanethioate (III), are both composed of a S-ethyl 2-phenylbutanethioate moiety but have different geometries. Compound I is substituted in the 3 and 4 positions by a hydroxyl group and a chlorine atom, respectively. In compound III the hydroxyl group in the 3 position of rac-(2R*,3R*)-S-ethyl-3-hydroxy-2-phenylbuthanethioate (II), has been tosylated in order to obtain suitable crystals for X-ray analysis. In compound I the phenyl substituent and the hydroxyl group have a syn arrangement, whereas in the tosylate derivative of II, i.e., compound III, they have an anti arrangement. In the crystal structure of I centrosymmetric hydrogen bonded dimers are formed via O–H•••O hydrogen bonds, involving the hydroxyl group and the carbonyl O-atom. In the crystal structure of III symmetry related molecules are connect via a weak C–H•••O intermolecular interaction, involving a tosylate O-atom and a phenyl H-atom, so forming zigzag chains propagating in the c direction. The compounds were prepared by the Mukaiyama crossed aldol reaction between the silyl enol ether of S-ethyl 2-phenylethanethioate and simple aldehydes, like 2-Chloroacetaldehyde (for I) and acetaldehyde (for II). The syn/anti stereo descriptors clearly indicate that the stereoselectivity of the Mukaiyama aldol reaction has switched from a syn selective process for the reaction using 2-Chloroacetaldehyde to an anti selective process for the reaction with acetaldehyde. In both compounds the relative stereochemistry at the newly created chiral centers, positions 2 and 3, is R/R
James E Springate - One of the best experts on this subject based on the ideXlab platform.
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comparative toxicity of ifosfamide metabolites and protective effect of mesna and amifostine in cultured renal tubule cells
Toxicology in Vitro, 2003Co-Authors: Emad L Zaki, James E Springate, Mary TaubAbstract:Abstract Renal injury is a common side effect of the chemotherapeutic agent ifosfamide. Current evidence suggests that the ifosfamide metabolite Chloroacetaldehyde contributes to this nephrotoxicity. The present study examined the effects of Chloroacetaldehyde and acrolein, another ifosfamide metabolite, on rabbit proximal renal tubule cells in primary culture. The ability of the uroprotectant medications sodium 2-mercaptoethanesulfonate (mesna) and amifostine to prevent Chloroacetaldehyde- and acrolein-induced renal cell injury was also assessed. Chloroacetaldehyde and acrolein (25–200 M) produced dose-dependent declines in neutral red dye uptake, glucose transport and glutathione content. Chloroacetaldehyde was a more potent toxin than acrolein. Pretreatment of cells with the glutathione-depleting agent buthionine sulfoximine enhanced the toxicity of both Chloroacetaldehyde and acrolein while co-administration of mesna or amifostine prevented metabolite toxicity. These results support the hypothesis that Chloroacetaldehyde is responsible for ifosfamide-induced nephrotoxicity. The protective effect of mesna and amifostine in vitro contrasts with clinical experience showing that these medications do not eliminate ifosfamide nephrotoxicity.
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toxicity of ifosfamide and its metabolite Chloroacetaldehyde in cultured renal tubule cells
In Vitro Cellular & Developmental Biology – Animal, 1999Co-Authors: James E Springate, Kenneth K Chan, Sherry R Davies, Mary TaubAbstract:Renal injury is a common side effect of the chemotherapeutic agent ifosfamide. Current evidence suggests that the ifosfamide metabolite Chloroacetaldehyde may contribute to this nephrotoxicity. The present study examined the effects of ifosfamide and Chloroacetaldehyde on rabbit proximal renal tubule cells in primary culture. The ability of the uroprotectant medication sodium 2-mercaptoethanesulfonate (mesna) to prevent Chloroacetaldehyde-induced renal cell injury was also assessed. Chloroacetaldehyde (12.5-150 microM) produced dose-dependent declines in neutral red dye uptake, ATP levels, glutathione content, and cell growth. Coadministration of mesna prevented Chloroacetaldehyde toxicity while pretreatment of cells with the glutathione-depleting agent buthionine sulfoximine enhanced the toxicity of Chloroacetaldehyde. Ifosfamide (1000-10,000 microM) toxicity was detected only at concentrations of 4000 microM or greater. Analysis of media collected from ifosfamide-treated cell cultures revealed the presence of several ifosfamide metabolites, demonstrating that renal proximal tubule cells are capable of biotransforming this chemotherapeutic agent. This primary renal cell culture system should prove useful in studying the cause and prevention of ifosfamide nephrotoxicity.
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ifosfamide metabolite Chloroacetaldehyde causes renal dysfunction in vivo
Journal of Applied Toxicology, 1997Co-Authors: James E SpringateAbstract:Renal injury is a common side-effect of the chemotherapeutic agent ifosfamide. Current evidence suggests that the ifosfamide metabolite Chloroacetaldehyde may be responsible for this nephrotoxicity. The present study examined the effect of increasing amounts of intrarenally infused Chloroacetaldehyde on kidney function, glutathione content and malondialdehyde formation. The ability of the uroprotectant medication sodium 2-mercaptoethanesulfonate (mesna) to prevent Chloroacetaldehyde-induced renal injury was also assessed. Intrarenal Chloroacetaldehyde infusion caused dose-dependent declines in glomerular filtration rate and p-aminohippuric acid clearance and increases in urine flow rate, sodium, glucose and protein excretion. These abnormalities were associated with progressive kidney glutathione depletion and malondialdehyde accumulation. Mesna infusion did not affect renal function but did cause a significant fall in kidney glutathione content. Simultaneous administration of Chloroacetaldehyde and mesna only partially corrected renal functional abnormalities and prevented malondialdehyde accumulation but not glutathione depletion. These results show that the ifosfamide metabolite Chloroacetaldehyde causes kidney dysfunction, glutathione depletion and lipid peroxidation in vivo. Mesna provides limited protection against Chloroacetaldehyde nephrotoxicity, potentially explaining its inability to completely prevent ifosfamide-related renal injury in clinical practice.