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At least 19 recordsLinked to original sources
PubMed1980

Mutagenic activity of vinyl compounds and derived epoxides.

Many vinyl compounds, such as vinyl chloride and some inhalational anesthetics, are known to be mutagens. In the present study, 10 vinyl compounds or derived epoxides, widely used in industry, were assayed in the Salmonella typhimurium/mammalian microsome system. 3 strains of histidine-dependent S. typhimurium, TA1535, TA98 and TA100 were used. Of the 10 compounds, 4 were mutagens. They were 9-vinylanthracene, vinylcarbazole, 3-vinyl-7-oxabicyclo[4.1.0]heptane and 3-epoxyethyl-7-oxabicyclo[4.1.0]-heptane. The study confirmed the overall genotoxicity of vinyl compounds and epoxides and the need to carefully screen them for mutagenic/carcinogenic effects.

Mutagenicity Tests↗
PubMed2003

Ozonolysis of vinyl compounds, CH2=CH-X, in aqueous solution--the chemistries of the ensuing formyl compounds and hydroperoxides.

Reactions of ozone with some vinyl compounds of the general structure CH2=CH-X were studied in aqueous solution. Rate constants (in brackets, unit: dm3 mol-1 s-1) were determined: acrylonitrile (670), vinyl acetate (1.6 x 10(5)), vinylsulfonic acid (anion, 8.3 x 10(3)), vinyl phenylsulfonate (ca. 200), vinyl diethylphosphonate (3.3 x 10(3)), vinylphosphonic acid (acid, 1 x 10(4); mono-anion, 2.7 x 10(4); di-anion, 1 x 10(5)), vinyl bromide (1 x 10(4)). The main pathway leads to the formation of HOOCH2OH and HC(O)X. As measured by stopped flow with conductometric detection, the latter one may undergo rapid hydrolysis by water, e.g. HC(O)CN (3 s-1). Other HC(O)X hydrolyse much slower, e.g. HC(O)PO3(Et)2 (7 x 10(-3) s-1) and HC(O)P(OH)O2- (too slow to be measured). The OH(-)-induced hydrolyses range from ca. 5 dm3 mol-1 s-1 [HC(O)PO(3)2-] to 3.8 x 10(5) dm3 mol-1 s-1 [HC(O)CN]. HC(O)Br mainly decomposes rapidly (too fast for the determination of the rate) into CO and Br- plus H+, and the competing hydrolysis is of minor importance (3.7%). The slow hydrolysis of HC(O)PO(3)2- at pH 10.2, where HOOCH2OH is rapidly decomposed into CH2O plus H2O2, allows an H2O2-induced decomposition (k = 260 dm3 mol-1 s-1) to take place. Formate and phosphate are the final products.

Journal Article↗
PubMed1980

Mutagenicity of vinyl compounds in Salmonella typhimurium.

Eighteen compounds structurally related to the mutagenic carcinogen vinyl chloride have been tested for mutagenicity in five strains of Salmonella typhimurium. Acrolein, acrolein diethylacetal, acrylonitrile, allyl alcohol, allyl bromide, crotonaldehyde, crotyl alcohol, and vinyl bromide were mutagenic with one or more strains; acrolein bisulfite, acrolein oxime, acrylamide, acrylic acid, allylamine, trans-cinnamaldehyde, trans-cinnamic acid, crotonic acid, methyl methacrylate, and vinyl acetate were not mutagenic. The mutagenicity tests were performed both without and with activation by rat and hamster liver microsomal preparations (S9). All compounds were tested in the plate incorporation and/or liquid preincubation tests except vinyl bromide, which was tested as a gas.

Animals↗
PubMed1978

A water-extractable toxic compound in vinyl upholstery fabric.

A compound, highly toxic to goldfish, was found to be released from a vinyl (polyvinyl chloride) automotive upholstery fabric when the material was immersed in their water. The compound, a flame retardant used in such material, was identified by specific detector gas chromatography and mass spectrometry as triphenyl phosphate. Fish exposed to the immersed fabric or pure triphenyl phosphate showed neurologic intoxication and extensive histopathologic lesions.

Animals↗
PubMed1980

[Thromboresistent properties of hydrophilic gels].

Thromboresistant properties of hydrophilic gels prepared on the basis of copolymers of nitrogen-containing heterocyclic vinyl compounds with vinyl monomers have been investigated. Hydrophilic gels prevent fibrinogen adsorption, activation of procoagulants and adhesion of platelets. Hydrogel surfaces possess selective tropism for plasma albumin. It is believed that the thromboresistant effect of the hydrophilic gels is consequent on the competitive action of plasma albumin. Modification of the gels leads to the improvement of their thromboresistant properties.

Animals↗
PubMed2001

Measuring concentrations of volatile organic compounds in vinyl flooring.

The initial solid-phase concentration of volatile organic compounds (VOCs) is a key parameter influencing the emission characteristics of many indoor materials. Solid-phase measurements are typically made using solvent extraction or thermal headspace analysis. The high temperatures and chemical solvents associated with these methods can modify the physical structure of polymeric materials and, consequently, affect mass transfer characteristics. To measure solid-phase concentrations under conditions resembling those in which the material would be installed in an indoor environment, a new technique was developed for measuring VOC concentrations in vinyl flooring (VF) and similar materials. A 0.09-m2 section of new VF was punched randomly to produce -200 0.78-cm2 disks. The disks were milled to a powder at -140 degrees C to simultaneously homogenize the material and reduce the diffusion path length without loss of VOCs. VOCs were extracted from the VF particles at room temperature by fluidized-bed desorption (FBD) and by direct thermal desorption (DTD) at elevated temperatures. The VOCs in the extraction gas from FBD and DTD were collected on sorbent tubes and analyzed by gas chromatography/mass spectrometry (GC/MS). Seven VOCs emitted by VF were quantified. Concentration measurements by FBD ranged from 5.1 microg/g VF for n-hexadecane to 130 microg/g VF for phenol. Concentrations measured by DTD were higher than concentrations measured by FBD. Differences between FBD and DTD results may be explained using free-volume and dual-mobility sorption theory, but further research is necessary to more completely characterize the complex nature of a diffusant in a polymer matrix.

Air Pollution, Indoor↗
PubMed1987

Immunogenicity of acrylate chemicals as assessed by antibody induction.

The immunogenicities of two acrylate chemicals, trimethylolpropane triacrylate (TMPTA) and methyl acrylate (MeAc), and one related vinyl compound, 4-vinyl pyridine (4VP), were investigated by determining the in vivo induction of IgG antibodies in guinea pigs. The injection of the chemicals emulsified in Freund's complete adjuvant resulted in the induction of serum antibody responses against MeAc and 4VP but not TMPTA. However, antibody with anti-TMPTA activity was produced following immunization of guinea pigs with TMPTA conjugated to protein, which allowed comparisons to be made of the immunogenic structural features of the compounds.

Acrylates↗
PubMed2002

Predicting the emission rate of volatile organic compounds from vinyl flooring.

A model for predicting the rate at which a volatile organic compound (VOC) is emitted from a diffusion-controlled material is validated for three contaminants (n-pentadecane, n-tetradecane, and phenol) found in vinyl flooring (VF). Model parameters are the initial VOC concentration in the material phase (C0), the material/air partition coefficient (K), and the material-phase diffusion coefficient (D). The model was verified by comparing predicted gas-phase concentrations to data obtained during small-scale chamber tests and by comparing predicted material-phase concentrations to those measured at the conclusion of the chamber tests. Chamber tests were conducted with the VF placed top-side-up and bottom-side-up. With the exception of phenol and within the limits of experimental precision, the mass of VOCs recovered in the gas-phase balances the mass emitted from the material phase. The model parameters (C0, K, and D) were measured using procedures completely independent of the chamber test. Gas- and material-phase predictions compare well to the bottom-side-up chamber data. The lower emission rates for the top-side-up orientation may be explained by the presence of a low-permeability surface layer. The sink effect of the stainless steel chamber surface was shown to be negligible.

Air Pollution, Indoor↗
PubMed1981

Nephrotoxicity of halogenated vinyl cysteine compounds.

S-(1,2-dichlorovinyl) cysteine (DCVC), is a potent nephrotoxin. In order to determine if other vinyl cysteine conjugates were nephrotoxic, halogenated vinyl cysteines, HVC-1 and HVC-2, were prepared from chlorotrifluoroethylene (CTFE), a fluorocarbon monomer, or chlorotifluoroethylene, a metabolite of halothane, respectively. Three days after receiving DCVC (5-10 mg/kg), CD-1 mice developed focal renal tubular necrosis. Mice treated with HVC-1 or HVC-2 (5-10 mg/kg) also developed renal necrosis by 3 days post exposure. HVC-1 was not as potent as DCVC with the necrosis limited to the pars recta. At equivalent doses HVC-2 caused less necrosis of the pars recta than HVC-1. The degree of nephrotoxicity by all three compounds exhibited a dose-response from 1-25 mg/kg. Doses greater than 25 mg/kg were often lethal within 3 days and the mice had a complete zonal necrosis of the renal cortex and a two-fold increase in kidney weight. Structural analogues, S-(chlorethyl) or S-(hydroxyethyl) cysteine, did not cause renal necrosis in mice at doses up to 200 mg/kg. These studies indicate that the enzymes reportedly responsible for converting DCVC to a nephrotoxic intermediate will also bioactivate other halogenated vinyl cysteines.

Animals↗
PubMed2005

Gene expression profiling of nephrotoxicity from the sevoflurane degradation product fluoromethyl-2,2-difluoro-1-(trifluoromethyl)vinyl ether ("compound A") in rats.

The major degradation product of the volatile anesthetic sevoflurane, the haloalkene fluoromethyl-2,2-difluoro-1-(trifluoromethyl)vinyl ether (FDVE or "compound A"), is nephrotoxic in rats. FDVE undergoes complex metabolism and bioactivation, which mediates the nephrotoxicity. Nevertheless, the molecular and cellular mechanisms of FDVE toxification are unknown. This investigation evaluated the gene expression profile of kidneys in rats administered a nephrotoxic dose of FDVE. Male Fischer 344 rats (five per group) received 0.25 mmol/kg intraperitoneal FDVE or corn oil (controls) and were sacrificed after 24 or 72 h. Urine output and kidney histological changes were quantified. Kidney RNA was extracted for microarray analysis using Affymetrix GeneChip Rat Expression Array 230A arrays. Quantitative real-time PCR confirmed the modulation of several genes. FDVE caused significant diuresis and necrosis at 24 h, with normal urine output and evidence of tubular regeneration at 72 h. There were 517 informative genes that were differentially expressed >1.5-fold (p < 0.05) versus control at 24 h, of which 283 and 234 were upregulated and downregulated, respectively. Major classes of upregulated genes included those involved in apoptosis, oxidative stress, and inflammatory response (mostly at 24 h), and regeneration and repair; downregulated genes were generally associated with transporters and intermediary metabolism. Among the quantitatively most upregulated genes were kidney injury molecule, osteopontin, clusterin, tissue inhibitor of metalloproteinase 1, and TNF receptor 12, which have been associated with other forms of nephrotoxicity, and angiopoietin-like protein 4, glycoprotein nmb, ubiquitin hydrolase, and HSP70. Microarray results were confirmed by quantitative real-time PCR. FDVE causes rapid and brisk changes in gene expression, providing potential insights into the mechanism of FDVE toxification, and potential biomarkers for FDVE nephrotoxicity which are more sensitive than conventional measures of renal function.

Anesthetics, Inhalation↗
PubMed1992

Sister-chromatid exchanges induced by vinyl esters and respective carboxylic acids in cultured human lymphocytes.

Vinyl acetate--an efficient inducer of sister-chromatid exchanges (SCEs)--is known to be hydrolyzed in mammalian cells into acetic acid and acetaldehyde, the latter being the likely metabolite responsible for the SCE induction. As similar hydrolysis to acetaldehyde and to a carboxylic acid is also expected for other vinyl esters, five such compounds--vinyl formate, vinyl chloroformate, vinyl propionate, vinyl crotonate and vinyl-2-ethylhexanoate--and five carboxylic acids--formic acid, acetic acid, propionic acid, crotonic acid and 2-ethylhexanoic acid--were tested for their ability to induce SCEs in cultured (72 h) human lymphocytes with a 48-h treatment, starting at 24 h after culture initiation. Vinyl formate, vinyl propionate and vinyl crotonate induced a clear dose-dependent increase in the number of SCEs/cell at concentrations of 0.125-0.5 mM and vinyl chloroformate at 0.063-1 mM, i.e., at roughly the same concentration range as vinyl acetate and acetaldehyde. Vinyl-2-ethylhexanoate required slightly higher concentrations (0.25-4 mM) for SCE induction. All of the carboxylic acids tested also elevated SCEs, but only slightly. Formic acid and crotonic acid produced some SCE increase at a concentration of 10 mM, acetic acid at 5 and 10 mM and propionic acid at 2.5 mM. 2-Ethylhexanoic acid induced SCEs at a lower concentration range (0.63-2.5 mM) than the other acids. The positive concentrations of the first three carboxylic acids lowered the pH of the culture medium immediately after the treatment by 0.5-1.0 pH unit (lowest observed pH 6.53). The pH differences from the control cultures became smaller in measurements done 24 h and 48 h after the beginning of treatment. Propionic acid and 2-ethylhexanoic acid affected medium pH only slightly (maximum drop 0.2 pH units) at the concentrations that induced SCEs. The results lend support to the idea that the efficient SCE induction observed with the vinyl esters results from the formation of acetaldehyde, with carboxylic acids--with the possible exception of 2-ethylhexanoic acid--playing no significant role. The slight SCE induction obtained with the carboxylic acids cannot be explained by lowered pH alone.

Carboxylic Acids↗
PubMed2003

Cytotoxicity of S-conjugates of the sevoflurane degradation product fluoromethyl-2,2-difluoro-1-(trifluoromethyl) vinyl ether (Compound A) in a human proximal tubular cell line.

Fluoromethyl-2,2-difluoro-1-(trifluoromethyl)vinyl ether (FDVE) is a fluorinated alkene formed by degradation of the volatile anesthetic sevoflurane in anesthesia machines. FDVE is nephrotoxic in rats but not humans. Rat FDVE nephrotoxicity is attributed to FDVE glutathione conjugation and bioactivation of subsequent FDVE-cysteine S-conjugates, in part by renal beta-lyase. Although FDVE conjugation and metabolism occur in both rats and humans, the mechanism for selective toxicity in rats and lack of effect in humans is incompletely elucidated. This investigation measured FDVE S-conjugate cytotoxicity in cultured human proximal tubular HK-2 cells, and compared this with known cytotoxic S-conjugates. HK-2 cells were incubated with FDVE and its GSH, cysteine S-mercapturic acid, cysteine S-sulfoxide, and mercapturic acid sulfoxide conjugates (0.1-2.7 mM) for 24 h. Cytotoxicity was determined by lactate dehydrogenase (LDH) release, total LDH, and the ability of viable cells to reduce a tetrazolium-based compound (MTT). FDVE was cytotoxic only at concentrations >/=0.9 mM. No increase in LDH release was observed with either FDVE-GSH conjugate. The FDVE-cysteine conjugates S-(1,1-difluoro-2-fluoromethoxy-2-(trifluoromethyl) ethyl)-L-cysteine (DFEC) and (Z)-S-(1-fluoro-2-fluoromethoxy-2-(trifluoromethyl) vinyl)-L-cysteine ((Z)-FFVC) caused significant differences in LDH release and MTT reduction only at 2.7 mM; (Z)-FFVC was slightly more cytotoxic. Both S-(1,1-difluoro-2-fluoromethoxy-2-(trifluoromethyl) ethyl)-L-cysteine sulfoxide (DFEC-SO) and (Z)-N-acetyl-S-(1-fluoro-2-fluoromethoxy-2-(trifluoromethyl) vinyl)-L-cysteine sulfoxide ((Z)-N-Ac-FFVC-SO) caused slightly greater changes in LDH release or total LDH than the corresponding equimolar DFEC and (Z)-N-acetyl-S-(1-fluoro-2-fluoromethoxy-2-(trifluoromethyl) vinyl)-L-cysteine ((Z)-N-Ac-FFVC) conjugates. In contrast to FDVE S-conjugates, S-(1,2-dichlorovinyl)-L-cysteine was markedly cytotoxic, at concentrations as low as 0.1 mM. These results show that human proximal tubular cells are relatively resistant to FDVE and FDVE S-conjugate cytotoxicity. This may partially explain the lack of FDVE nephrotoxicity in humans.

Anesthetics, Inhalation↗
PubMed1996

P450-dependent and nonenzymatic human liver microsomal defluorination of fluoromethyl-2,2-difluoro-1-(trifluoromethyl)vinyl ether (compound A), a sevoflurane degradation product.

The volatile anesthetic sevoflurane is degraded by strong bases in the carbon dioxide absorbent in clinical anesthesia machines to fluoromethyl-2,2-difluoro-1-(trifluoromethyl)vinyl ether (FDVE, also called "Compound A"). FDVE is nephrotoxic in rats, where it is extensively biotransformed. Patients undergoing sevoflurane anesthesia have been exposed to low inhaled concentrations of FDVE. Although sevoflurane renal toxicity under conditions of FDVE formation has not been reported, there is still considerable concern about FDVE metabolism in humans and the potential for FDVE nephrotoxicity. Sevoflurane undergoes P450-catalyzed liver microsomal defluorination. We tested the hypothesis that FDVE also undergoes human liver microsomal defluorination. Defluorination occurred both in the absence and presence of NADPH; rates of total and NADPH-dependent fluoride formation were 1.6 +/- 0.1 and 1 +/- 0.1 nmol.min-1.mg-1 protein (mean +/- SD), respectively, in four human livers. Enzymatic defluorination was linear with respect to time, protein concentration, and was saturable with respect to substrate concentration. NADPH-dependent, but not NADPH-independent, FDVE defluorination was partially inhibited by coumarin, orphenadrine, diethyldithlocarbamate, and 4-methypyrazole. Microsomes containing cDNA-expressed human P4502E1 exhibited substantial catalytic activity toward FDVE defluorination. Microsomal FDVE defluorination was significantly diminished in the presence of the parent anesthetic, sevoflurane, from 1.3 to 0.6 nmol.min-1.mg-1. These results show that FDVE undergoes both P450-catalyzed and nonenzymatic defluorination by human liver microsomes. P4502E1 is implicated in the enzymatic defluorination. Nonenzymatic defluorination may result from FDVE addition to protein thiols. Enzymatic and/or nonenzymatic defluorination may be etiologic factors in FDVE nephrotoxicity in rats. In contrast, P450-dependent FDVE defluorination may be of less clinical consequence in humans, because it is inhibited by the parent anesthetic, sevoflurane.

Anesthetics, Inhalation↗
PubMed2001

Glutathione S-conjugation of the sevoflurane degradation product, fluoromethyl-2,2-difluoro-1-(trifluoromethyl)vinyl ether (compound A) in human liver, kidney, and blood in vitro.

Fluoromethyl-2,2-difluoro-1-(trifluoromethyl)vinyl ether (FDVE) is a fluorinated alkene formed by degradation of the volatile anesthetic sevoflurane in anesthesia machines. FDVE is nephrotoxic in rats and undergoes glutathione-dependent conjugation to form two alkane (G1, G2) and two alkene glutathione S-conjugates (G3, G4), cleavage to cysteine S-conjugates, and beta-lyase-catalyzed metabolism to reactive thionoacyl fluorides, which may react with cellular macromolecules to cause nephrotoxicity. Although similar metabolites have been identified in human urine in vivo, little is known about sites and mechanisms of GSH conjugation in humans. This investigation quantified FDVE-GSH conjugates formed by human hepatic and renal microsomal and cytosolic fractions and blood in vitro. LC-MS/MS analysis identified all four GSH conjugates (G1-G4) formed in all human subcellular fractions. Quantitative analysis indicated that the relative order of formation was G2 > G1 > G4 > G3 with human liver and kidney subfractions. In blood, the order was G1 > G4 > G2 > G3. These results demostrate that FDVE undergoes GSH-dependent conjugation in human liver and kidney microsomes and cytosol as well as blood, which may account for the detection of corresponding mercapturic acids in the urine of patients exposed to FDVE.

Anesthetics, Inhalation↗
PubMed2004

Role of cytochrome P4503A in cysteine S-conjugates sulfoxidation and the nephrotoxicity of the sevoflurane degradation product fluoromethyl-2,2-difluoro-1-(trifluoromethyl)vinyl ether (compound A) in rats.

The volatile anesthetic sevoflurane is degraded to fluoromethyl-2,2-difluoro-1-(trifluoromethyl)vinyl ether (FDVE) in anesthesia machines. FDVE is nephrotoxic in rats. FDVE undergoes glutathione conjugation, subsequent conversion to cysteine and mercapturic acid conjugates, and cysteine conjugate metabolism by renal beta-lyase, which is a bioactivation pathway mediating nephrotoxicity in rats. Recent in vitro studies revealed cytochrome P4503A-catalyzed formation of novel sulfoxide metabolites of FDVE cysteine-S and mercapturic acid conjugates in rat liver and kidney microsomes. FDVE-mercapturic acid sulfoxides were more toxic than other FDVE conjugates to renal proximal tubular cells in culture. Nevertheless, the occurrence and toxicological significance of FDVE sulfoxides formation in vivo remain unknown. This investigation determined, in rats in vivo, the existence, role of P4503A, and nephrotoxic consequence of FDVE conjugates sulfoxidation. Rats were pretreated with dexamethasone, phenobarbital, troleandomycin, or nothing (controls) before FDVE, and then, nephrotoxicity, FDVE-mercapturate sulfoxide urinary excretion, and FDVE-mercapturate sulfoxidation by liver microsomes were assessed. The formation of FDVE-mercapturic acid sulfoxide metabolites in vivo and their urinary excretion were unambiguously established by mass spectrometry. Dexamethasone and phenobarbital increased, and troleandomycin decreased (i) liver microsomal FDVE-mercapturic acid sulfoxidation in vitro, (ii) FDVE-mercapturic acid sulfoxide urinary excretion in vivo, and (iii) FDVE nephrotoxicity in vivo assessed by renal histology, blood urea nitrogen concentrations, and urine volume and protein excretion. Urine 3,3,3-trifluoro-2-(fluoromethoxy)propanoic acid, reflecting beta-lyase-dependent FDVE-cysteine S-conjugates metabolism, was minimally affected by the pretreatments. These results demonstrate that FDVE S-conjugates undergo P4503A-catalyzed sulfoxidation in rats in vivo, and this sulfoxidation pathway contributes to nephrotoxicity. FDVE S-conjugates sulfoxidation constitutes a newly discovered mechanism of FDVE bioactivation and toxicification in rats, in addition to beta-lyase-catalyzed metabolism of FDVE-cysteine S-conjugates.

Anesthetics, Inhalation↗
PubMed2004

Sulfoxidation of cysteine and mercapturic acid conjugates of the sevoflurane degradation product fluoromethyl-2,2-difluoro-1-(trifluoromethyl)vinyl ether (compound A).

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 inhibitor 1-aminobenzotriazole completely inhibited S-oxidation, while heating to inactivate FMO decreased (Z)-N-Ac-FFVC and N-Ac-DFEC sulfoxidation only 0 and 30%, respectively. Of the various cytochrome P450s examined, P450s 3A4 and 3A5 had the highest S-oxidase activity toward (Z)-N-Ac-FFVC; P450 3A4 was the predominant enzyme forming N-Ac-DFEC-SO. The P450 3A inhibitors troleandomycin and ketoconazole inhibited >95% of (Z)-N-Ac-FFVC sulfoxidation by P450 3A4 and 3A5 and 40-100% of (Z)-N-Ac-FFVC sulfoxidation by human liver microsomes and 15-85% of N-Ac-DFEC sulfoxidation by human liver microsomes. Sulfoxidation of DFEC was also examined in human liver microsomes. Substantial amounts of sulfoxide were observed, even in the absence of NADPH or protein, while enzymatic formation was comparatively minimal. These results show that FDVE S-conjugates undergo P450-catalyzed and nonenzymatic sulfoxidation and that enzymatic sulfoxidation of (Z)-N-Ac-FFVC and N-Ac-DFEC is catalyzed predominantly by P450 3A. The extent of FDVE sulfoxidation in vivo and the toxicologic significance of FDVE sulfoxides remain unknown and merit further investigation.

Acetylcysteine↗
PubMed1996

Evidence for metabolism of fluoromethyl 2,2-difluoro-1-(trifluoromethyl)vinyl ether (compound A), a sevoflurane degradation product, by cysteine conjugate beta-lyase.

The volatile anesthetic sevoflurane is degraded to fluoromethyl 2,2-difluoro-1-(trifluoromethyl)vinyl ether (FDVE), a potent rat nephrotoxin. In rats in vivo, FDVE undergoes glutathione conjugation and metabolism to cysteine conjugates, whose bioactivation by renal cysteine conjugate beta-lyase has been implicated by the protective effects of (aminooxy)acetic acid, an inhibitor of cysteine conjugate beta-lyase. We specifically tested the hypothesis that FDVE is metabolized via the beta-lyase pathway to yield 3,3,3-trifluoro-2-(fluoromethoxy)propanoic acid. Urine of rats administered FDVE (0.3 mmol/kg) was extracted and derivatized with diazomethane. Headspace GC/MS analysis demonstrated a peak whose retention time and mass spectrum were identical to those of synthetic methyl 3,3,3-trifluoro-2-(fluoromethoxy)-propanoate. Pretreatment of rats with (aminooxy)acetic acid significantly decreased the amount of 3,3,3-trifluoro-2-(fluoromethoxy)propanoic acid detected in the urine of FDVE-treated animals. The 19F NMR spectrum of urine from rats administered FDVE was consistent with the formation of 3,3,3-trifluoro-2-(fluoromethoxy)propanoic acid, but could not be differentiated from that of FDVE mercapturates, which are also excreted in urine. These results suggest that FDVE undergoes biotransformation via the beta-lyase pathway and beta-lyase-catalyzed metabolism may mediate the nephrotoxicity of this compound.

Aminooxyacetic Acid↗