Identification of a unique glutathione conjugate of trichloroacrolein using heteronuclear multiple quantum coherence carbon-13 nuclear magnetic resonance spectroscopy

Hackett, Amy G.; Kotyk, John J.; Fujiwara, Hideji; Logusch, Eugene W.

doi:10.1021/ja00165a068

Cited by 9 publications

(7 citation statements)

References 2 publications

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“…2 is converted to 5 in 57 % yield at 15-30 min by the MFO system, and 5 in turn presumably yields 9 (Figure 1) which, although not detected, would hydrolyze to chloroacrylic acid, a known metabolite of 2 (Marsden and Casida, 1982). The primary route for mutagen formation appears to be the conversion of 2 to 8 by S-methylene hydroxylation (Hackett et al, 1990;Marsden and Casida, 1982) rather than a reaction sequence initiated by sulfoxidation. The detoxifying activity of GSH is therefore primarily via direct reaction with 8 (Hackett et al, 1990) rather than with 5.…”

Section: Discussionmentioning

confidence: 93%

“…On the other hand, 4b yields more 10 than 4a possibly because of its greater stability to the rearrangementelimination reactions. Coupling of 6 and 8 with GSH involves Michael addition (Hackett et al, 1990;Segall et al, 1985).…”

Section: Discussionmentioning

confidence: 99%

“…One volatile mutagenic metabolite of 1, i.e., 2-chloroacrolein (6), is identified by TLC as the 2,4-dinitrophenylhydrazone in 1.6% yield (Schuphan and Casida, 1979a,b). Metabolism of 2 in a microsome plus NADPH system alone or with GSH yields metabolites derived from 8 as an intermediate, indicating activation by S-methylene hydroxylation (Hackett et al, 1990;Marsden and Casida, 1982). Dithiocarbamate 3 is metabolized in an MFO system to 6 analyzed as above in 0.6% yield (Rosen et al, 1980a), again suggesting allylic hydroxylation as the source of the mutagen (Rosen et al, 1980a; Schuphan et al, 1979).…”

Section: Introductionmentioning

confidence: 99%

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Diallate, triallate, and sulfallate herbicides: identification of thiocarbamate sulfoxides, chloroacroleins, and chloroallylthiols as mouse microsomal oxidase and glutathione S-transferase metabolites

Mair¹,

Casida²

1991

J. Agric. Food Chem.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Diallate, triallate, and sulfallate herbicides: identification of thiocarbamate sulfoxides, chloroacroleins, and chloroallylthiols as mouse microsomal oxidase and glutathione S-transferase metabolites

Mair¹,

Casida²

1991

J. Agric. Food Chem.

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“…The incubation of trichloroacrolein, another R, -unsaturated compound, with GSH also gave rise to mono-and di-GSH adducts (25). The mechanism behind the formation of adducts 1-4 involves a Michael addition of the NAC molecule to DCVCS followed by elimination of HCl ( Figure 6).…”

Section: Discussionmentioning

confidence: 99%

Formation of Three N-Acetyl-l-cysteine Monoadducts and One Diadduct by the Reaction of S-(1,2-Dichlorovinyl)-l-cysteine Sulfoxide with N-Acetyl-l-cysteine at Physiological Conditions: Chemical Mechanisms and Toxicological Implications

Barshteyn

Elfarra

2007

Chem. Res. Toxicol.

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Previously, our laboratory has shown that S-(1,2-dichlorovinyl)-L-cysteine sulfoxide (DCVCS), a Michael acceptor produced by a flavin-containing monooxygenase 3 (FMO3)-mediated oxidation of S-(1,2-dichlorovinyl)-L-cysteine (DCVC), is a more potent nephrotoxicant than DCVC. In the present study, we characterized reactions of DCVCS with nucleophilic amino acids. DCVCS incubations with N-acetyl-L-cysteine (NAC) at pH 7.4 and 37 degrees C for 1 h resulted in the formation of three monoadducts and one diadduct characterized by LC/MS, 1H NMR, and 1H-detected heteronuclear single quantum correlation. The formation of all adducts (with relative ratios of 29, 31, 24, and 12%, respectively) was rapid and time-dependent; the half-lives of the two DCVCS diastereomers in the presence of NAC were 13.8 (diastereomer I) and 9.4 min (diastereomer II). Adducts 1 and 2 were determined to be diastereomers of S-[1-chloro-2-(N-acetyl-L-cystein- S-yl)vinyl]-L-cysteine sulfoxide formed by Michael addition of NAC to the terminal vinylic carbon of DCVCS followed by loss of HCl. Adduct 4 was determined to be S-[2-chloro-2-(N-acetyl-L-cystein- S-yl)vinyl]-L-cysteine sulfoxide formed from the initial Michael addition product followed by a less favorable loss of HCl and/or by a rearrangement of adduct 2 through the formation of a cyclic chloronium ion. The addition of another molecule of NAC to monoadducts 1, 2, or 4 resulted in the formation of the novel diadduct, S-[2,2-( N-acetyl-L-cystein-S-yl)vinyl]-L-cysteine sulfoxide (adduct 3), whose detection in relatively large amount suggests that DCVCS could act as a cross-linking agent. DCVCS was not reactive with N-acetyl-L-lysine or L-valinamide at similar incubation conditions. Collectively, the results suggest selective reactivity of DCVCS toward protein sulfhydryl groups. Furthermore, the cross-linking properties of DCVCS may in part explain its high nephrotoxic potency.

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“…Alternatively, specifically 13C-enriched substrates are used. In the latter case, 1H-13C shift-correlated NMR spectroscopy (16,17) or techniques of selective observation of resonances from hydrogens directly bound to 13C atoms were applied (18,19). Among these techniques, proton-detected heteronuclear multiple-quantum coherence (HMQC) NMR seems to be the method of choice, if high sensitivity is required (19).…”

mentioning

confidence: 99%

Metabolic pathways of 1-butyl [3-13C]acrylate. Identification of urinary metabolites in rat using nuclear magnetic resonance and mass spectroscopy

Linhart

Hrabal²,

Šmejkal³

et al. 1994

Chem. Res. Toxicol.

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1-Butylacrylate, an industrial monomer, is rapidly metabolized by carboxylesterase-catalyzed hydrolysis to acrylic acid and 1-butanol. Acrylic acid enters the intermediary metabolism and is efficiently degraded to carbon dioxide as the metabolic end product. To obtain a virtually complete metabolic pattern, rats were dosed by a single intraperitoneal dose of 1 mmol/kg 1-butyl [3-13C]acrylate. The urine was then analyzed by a one-dimensional 1H-detected and two-dimensional 1H-13C shift-correlated heteronuclear multiple-quantum NMR experiment. In this experiment, three urinary metabolites, namely, 3-hydroxypropanoic acid, N-acetyl-S-(2-carboxyethyl)cysteine, and N-acetyl-S-(2-carboxyethyl)cysteine sulfoxide, were identified comparing their 1H and 13C chemical shifts with those of authentic standards. In another experiment, to enhance minor metabolic pathways, rats were dosed with 0.25 mmol/kg of a carboxylesterase inhibitor, tri-o-tolyl phosphate, prior to 0.5 mmol/kg butyl [3-13C]acrylate. Under these conditions, N-acetyl-S-(2-carboxyethyl)cysteine, N-acetyl-S-[2-(butoxycarbonyl)-ethyl]cysteine, and N-acetyl-S-(2-carboxyethyl)cysteine sulfoxide were found in urine. No metabolites which would arise from a possible metabolic activation of 1-butyl acrylate to 1-butyl oxiranecarboxylate and its subsequent hydrolysis or glutathione conjugation were found. It is estimated that any metabolite amounting to more than 1% of the dose should be detected under these conditions. To study the routes by which BA enters the intermediary metabolism, incorporation of the label into urinary carboxylic acids was followed by GC/MS. Significant enrichment was found in 3-hydroxypropanoic acid and citric and isocitric acid but not in lactic acid.(ABSTRACT TRUNCATED AT 250 WORDS)

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Identification of a unique glutathione conjugate of trichloroacrolein using heteronuclear multiple quantum coherence carbon-13 nuclear magnetic resonance spectroscopy

Cited by 9 publications

References 2 publications

Diallate, triallate, and sulfallate herbicides: identification of thiocarbamate sulfoxides, chloroacroleins, and chloroallylthiols as mouse microsomal oxidase and glutathione S-transferase metabolites

Diallate, triallate, and sulfallate herbicides: identification of thiocarbamate sulfoxides, chloroacroleins, and chloroallylthiols as mouse microsomal oxidase and glutathione S-transferase metabolites

Formation of Three N-Acetyl-l-cysteine Monoadducts and One Diadduct by the Reaction of S-(1,2-Dichlorovinyl)-l-cysteine Sulfoxide with N-Acetyl-l-cysteine at Physiological Conditions: Chemical Mechanisms and Toxicological Implications

Metabolic pathways of 1-butyl [3-13C]acrylate. Identification of urinary metabolites in rat using nuclear magnetic resonance and mass spectroscopy

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