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Evan D. Kharasch - One of the best experts on this subject based on the ideXlab platform.
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Sulfoxidation of Cysteine and Mercapturic Acid Conjugates of the Sevoflurane Degradation Product Fluoromethyl-2,2-diFluoro-1-(triFluoromethyl)vinyl Ether (Compound A)
Chemical Research in Toxicology, 2004Co-Authors: T. Gul Altuntas, Sang B. Park, Evan D. KharaschAbstract:The volatile anesthetic sevoflurane is degraded in anesthesia machines to the haloalkene Fluoromethyl-2,2-diFluoro-1-(triFluoromethyl)vinyl ether (FDVE), which can cause renal and hepatic toxicity in rats. FDVE is metabolized to S-[1,1-diFluoro-2-Fluoromethoxy-2-(triFluoromethyl)ethyl]-l-cysteine (DFEC) and (E) and (Z)-S-[1-Fluoro-2-Fluoromethoxy-2-(triFluoromethyl)vinyl]-l-cysteine [(E,Z)-FFVC], which are N-acetylated to N-Ac-DFEC and (E,Z)-N-Ac-FFVC S-conjugates. Some haloalkene S-conjugates undergo sulfoxidation. This investigation tested the hypothesis that FDVE S-conjugates can also undergo sulfoxidation, by evaluating sulfoxide formation by human and rat liver and kidney microsomes and expressed P450s and flavin monooxygenases. Rat, and at lower rates human, liver microsomes oxidized (Z)-N-Ac-FFVC and N-Ac-DFEC to the corresponding sulfoxides. Much lower rates of (Z)-N-Ac-FFVC, but not N-Ac-DFEC, sulfoxidation occurred with rat and human kidney microsomes. In human liver microsomes, the P450 inhibit...
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dose dependent metabolism of Fluoromethyl 2 2 diFluoro 1 triFluoromethyl vinyl ether compound a an anesthetic degradation product to mercapturic acids and 3 3 3 triFluoro 2 Fluoromethoxy propanoic acid in rats
Toxicology and Applied Pharmacology, 1999Co-Authors: Evan D. Kharasch, Carole Jubert, Douglas K Spracklin, Gary M HoffmanAbstract:Abstract The volatile anesthetic sevoflurane is degraded in anesthesia machines to Fluoromethyl-2,2-diFluoro-1-(triFluoromethyl)vinyl ether (FDVE), to which humans are exposed. FDVE is metabolized in rats and humans to two alkane and two alkene glutathione S-conjugates that are hydrolyzed to the corresponding cysteine S -conjugates. The latter are N-acetylated to mercapturic acids, or bioactivated by renal cysteine conjugate β-lyase to metabolites which may react with cellular macromolecules or hydrolyze to 3,3,3-triFluoro-2-(Fluoromethoxy)propanoic acid. FDVE causes nephrotoxicity in rats, which evidence suggests is mediated by renal uptake of FDVE S -conjugates and metabolism by β-lyase. Although pathways of FDVE metabolism have been described qualitatively, the purpose of this investigation was to quantify FDVE metabolism via mercapturic acid and β-lyase pathways. Fischer 344 rats underwent 3-h nose-only exposure to FDVE (0 ± 0, 46 ± 19, 98 ± 7, 150 ± 29, and 220 ± 40 ppm), and urine was collected for 24 h. Urine concentrations of the mercapturates, N- acetyl- S -(1,1,3,3,3-pentaFluoro-2-Fluoromethoxypropyl)- l -cysteine and N- acetyl- S -(1-Fluoro-2-Fluoromethoxy-2-(triFluoromethyl)vinyl)- l -cysteine, the β-lyase-dependent metabolite 3,3,3-triFluoro-2-(Fluoromethoxy)propanoic acid, and its degradation product triFluorolactic acid, were determined by GC/MS. There was dose-dependent urinary excretion of the alkane mercapturate N- acetyl- S -(1,1,3,3,3-pentaFluoro-2-Fluoromethoxypropyl)- l -cysteine and 3,3,3-triFluoro-2-(Fluoromethoxy)propanoic acid, while excretion of the alkene mercapturate N- acetyl- S -(1-Fluoro-2-Fluoromethoxy-2-(triFluoromethyl)vinyl)- l -cysteine plateaued at higher FDVE exposures. The alkane:alkene mercapturic acid excretion ratio was between 2:1 and 4:1. TriFluorolactic acid was only rarely observed. Urine excretion of the β-lyase-dependent metabolite 3,3,3-triFluoro-2-(Fluoromethoxy)propanoic acid was 10-fold greater than that of the combined mercapturates. Results show that FDVE cysteine S -conjugates undergo facile metabolism via renal β-lyase, particularly in comparison with detoxication by mercapturic acid formation. The quantitative assay developed herein may provide a biomarker for FDVE exposure and relative metabolism via toxification and detoxifying pathways, applicable to animal and human investigations.
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identification in rat bile of glutathione conjugates of Fluoromethyl 2 2 diFluoro 1 triFluoromethyl vinyl ether a nephrotoxic degradate of the anesthetic agent sevoflurane
Chemical Research in Toxicology, 1996Co-Authors: Margaret R Davis, Evan D. Kharasch, George A Doss, Thomas A BaillieAbstract:Recent studies have indicated that the nephrotoxicity of Fluoromethyl 2,2-diFluoro-1-(triFluoromethyl)vinyl ether (“Compound A”), a breakdown product of the inhaled anesthetic sevoflurane, may be mediated by a reactive intermediate(s) generated via the cysteine conjugate β-lyase pathway. In order to gain a better understanding of glutathione (GSH)-dependent metabolism of Compound A, the present study was carried out with the primary goal of detecting and characterizing Compound A−GSH conjugates. By means of ionspray LC-MS/MS and NMR spectroscopy, a total of four GSH conjugates (“A1−A4”) were identified from the bile of rats dosed intraperitoneally with Compound A. A1 and A2 were identified as two diastereomers of S-[1,1-diFluoro-2-(Fluoromethoxy)-2-(triFluoromethyl)ethyl]glutathione, while A3 and A4 were identified as (E)- and (Z)-S-[1-Fluoro-2-(Fluoromethoxy)-2-(triFluoromethyl)vinyl]glutathione, respectively. Quantitative analyses indicated that approximately 29% of the administered dose of Compound A w...
Thomas A Baillie - One of the best experts on this subject based on the ideXlab platform.
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identification in rat bile of glutathione conjugates of Fluoromethyl 2 2 diFluoro 1 triFluoromethyl vinyl ether a nephrotoxic degradate of the anesthetic agent sevoflurane
Chemical Research in Toxicology, 1996Co-Authors: Margaret R Davis, Evan D. Kharasch, George A Doss, Thomas A BaillieAbstract:Recent studies have indicated that the nephrotoxicity of Fluoromethyl 2,2-diFluoro-1-(triFluoromethyl)vinyl ether (“Compound A”), a breakdown product of the inhaled anesthetic sevoflurane, may be mediated by a reactive intermediate(s) generated via the cysteine conjugate β-lyase pathway. In order to gain a better understanding of glutathione (GSH)-dependent metabolism of Compound A, the present study was carried out with the primary goal of detecting and characterizing Compound A−GSH conjugates. By means of ionspray LC-MS/MS and NMR spectroscopy, a total of four GSH conjugates (“A1−A4”) were identified from the bile of rats dosed intraperitoneally with Compound A. A1 and A2 were identified as two diastereomers of S-[1,1-diFluoro-2-(Fluoromethoxy)-2-(triFluoromethyl)ethyl]glutathione, while A3 and A4 were identified as (E)- and (Z)-S-[1-Fluoro-2-(Fluoromethoxy)-2-(triFluoromethyl)vinyl]glutathione, respectively. Quantitative analyses indicated that approximately 29% of the administered dose of Compound A w...
Bruno Miguel Neves - One of the best experts on this subject based on the ideXlab platform.
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oxidative stress dependent activation of the eif2α atfr unfolded protein response branch by skin sensitizer 1 Fluoro 2 4 dinitrobenzene modulates dendritic like cell maturation and inflammatory status in a biphasic manner
Free Radical Biology and Medicine, 2014Co-Authors: Andreia Luis, Joao D Martins, Ana Maria Silva, Isabel C F R Ferreira, Maria Teresa Cruz, Bruno Miguel NevesAbstract:Abstract The pathogenesis of allergic contact dermatitis, the most common manifestation of immunotoxicity in humans, is intimately connected to hapten-induced maturation of dendritic cells (DC). The molecular mechanisms driving this maturational program are not completely known; however, initial danger signals such as the generation of reactive oxygen species (ROS) were shown to play a critical role. Recent evidence linking ROS production, endoplasmic reticulum (ER) stress, and the pathogenesis of several inflammatory diseases led us to analyze, in the present work, the ability of the skin sensitizer 1-Fluoro-2,4-dinitrobenzene (DNFB) to evoke ER stress in DC-like THP-1 cells and the concomitant consequences to their immunobiology. We found that DNFB triggers a ROS-dependent activation of the PERK–eIFα–ATF4 unfolded protein response (UPR) branch conferring cytoprotection and modulating the maturation/proinflammatory cell status in a biphasic manner. Early DNFB induction of ATF4 positively modulates autophagy-related genes MAP 1 LC 3 B and ATG 3 and stabilizes the transcription factor Nrf2, causing a strong induction of the HMOX 1-detoxifying gene. Moreover, we observed that in a first phase, DNFB-induced ATF4 upregulates IL 8 mRNA levels while blocking CD 86, IL 1 B , IL 12 B , and CXL 10 transcription. Later, following ATF4 decay, HMOX 1 and IL 8 transcription drastically decrease and CD 86, IL 1 B , and Il 12 B are upregulated. Overall, our results evidence a connection between sensitizer-induced redox imbalance and the establishment of ER stress in DC-like cells and provide new insights into the role of UPR effectors such as ATF4 to the complex DC maturational program.
Margaret R Davis - One of the best experts on this subject based on the ideXlab platform.
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identification in rat bile of glutathione conjugates of Fluoromethyl 2 2 diFluoro 1 triFluoromethyl vinyl ether a nephrotoxic degradate of the anesthetic agent sevoflurane
Chemical Research in Toxicology, 1996Co-Authors: Margaret R Davis, Evan D. Kharasch, George A Doss, Thomas A BaillieAbstract:Recent studies have indicated that the nephrotoxicity of Fluoromethyl 2,2-diFluoro-1-(triFluoromethyl)vinyl ether (“Compound A”), a breakdown product of the inhaled anesthetic sevoflurane, may be mediated by a reactive intermediate(s) generated via the cysteine conjugate β-lyase pathway. In order to gain a better understanding of glutathione (GSH)-dependent metabolism of Compound A, the present study was carried out with the primary goal of detecting and characterizing Compound A−GSH conjugates. By means of ionspray LC-MS/MS and NMR spectroscopy, a total of four GSH conjugates (“A1−A4”) were identified from the bile of rats dosed intraperitoneally with Compound A. A1 and A2 were identified as two diastereomers of S-[1,1-diFluoro-2-(Fluoromethoxy)-2-(triFluoromethyl)ethyl]glutathione, while A3 and A4 were identified as (E)- and (Z)-S-[1-Fluoro-2-(Fluoromethoxy)-2-(triFluoromethyl)vinyl]glutathione, respectively. Quantitative analyses indicated that approximately 29% of the administered dose of Compound A w...
T. Gul Altuntas - One of the best experts on this subject based on the ideXlab platform.
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Sulfoxidation of Cysteine and Mercapturic Acid Conjugates of the Sevoflurane Degradation Product Fluoromethyl-2,2-diFluoro-1-(triFluoromethyl)vinyl Ether (Compound A)
Chemical Research in Toxicology, 2004Co-Authors: T. Gul Altuntas, Sang B. Park, Evan D. KharaschAbstract:The volatile anesthetic sevoflurane is degraded in anesthesia machines to the haloalkene Fluoromethyl-2,2-diFluoro-1-(triFluoromethyl)vinyl ether (FDVE), which can cause renal and hepatic toxicity in rats. FDVE is metabolized to S-[1,1-diFluoro-2-Fluoromethoxy-2-(triFluoromethyl)ethyl]-l-cysteine (DFEC) and (E) and (Z)-S-[1-Fluoro-2-Fluoromethoxy-2-(triFluoromethyl)vinyl]-l-cysteine [(E,Z)-FFVC], which are N-acetylated to N-Ac-DFEC and (E,Z)-N-Ac-FFVC S-conjugates. Some haloalkene S-conjugates undergo sulfoxidation. This investigation tested the hypothesis that FDVE S-conjugates can also undergo sulfoxidation, by evaluating sulfoxide formation by human and rat liver and kidney microsomes and expressed P450s and flavin monooxygenases. Rat, and at lower rates human, liver microsomes oxidized (Z)-N-Ac-FFVC and N-Ac-DFEC to the corresponding sulfoxides. Much lower rates of (Z)-N-Ac-FFVC, but not N-Ac-DFEC, sulfoxidation occurred with rat and human kidney microsomes. In human liver microsomes, the P450 inhibit...
