Bioactivation mechanism of S-(3-oxopropyl)-N-acetyl-L-cysteine, the mercapturic acid of acrolein

Hashmi, M.; Vamvakas, Spyridon; Anders, M. W.

doi:10.1021/tx00027a007

Cited by 38 publications

(38 citation statements)

References 28 publications

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“…7). Similar results were obtained by Hashmi and colleagues [69], who observed release of acrolein from OPMA-S-oxide but not from OPMA under basic conditions. While both conjugates showed cytotoxicity in isolated rat renal proximal tubular cells, cytotoxicity was reduced for OPMA but not for its S-oxide when the cells were treated with methimazole, an inhibitor of flavin-containing monooxygenase (FMO).…”

Section: Glutathione Conjugation With Acroleinsupporting

confidence: 90%

“…While both conjugates showed cytotoxicity in isolated rat renal proximal tubular cells, cytotoxicity was reduced for OPMA but not for its S-oxide when the cells were treated with methimazole, an inhibitor of flavin-containing monooxygenase (FMO). The authors suggested that FMO-catalyzed S-oxygenation (bioactivation) of OPMA contributes to its cytotoxicity in the kidney [69], which would offer an explanation for the observed nephrotoxicity in rats given acrolein-GSH adduct intravenously [70] and possibly for acrolein's suspected involvement in cyclophosphamide-related urinary bladder cancer (acrolein is a metabolite of cyclophosphamide) [71]. In general, S-oxygenation can be mediated by cytochrome P450s and by FMOs.…”

Section: Glutathione Conjugation With Acroleinmentioning

confidence: 99%

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Acrolein: Sources, metabolism, and biomolecular interactions relevant to human health and disease

Stevens

Maier

2008

Molecular Nutrition Food Res

615

634

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Acrolein (2-propenal) is ubiquitously present in (cooked) foods and in the environment. It is formed from carbohydrates, vegetable oils and animal fats, amino acids during heating of foods, and by combustion of petroleum fuels and biodiesel. Chemical reactions responsible for release of acrolein include heat-induced dehydration of glycerol, retro-aldol cleavage of dehydrated carbohydrates, lipid peroxidation of polyunsaturated fatty acids, and Strecker degradation of methionine and threonine. Smoking of tobacco products equals or exceeds the total human exposure to acrolein from all other sources. The main endogenous sources of acrolein are myeloperoxidase-mediated degradation of threonine and amine oxidase-mediated degradation of spermine and spermidine, which may constitute a significant source of acrolein in situations of oxidative stress and inflammation. Acrolein is metabolized by conjugation with glutathione and excreted in the urine as mercapturic acid metabolites. Acrolein forms Michael adducts with ascorbic acid in vitro, but the biological relevance of this reaction is not clear. The biological effects of acrolein are a consequence of its reactivity towards biological nucleophiles such as guanine in DNA and cysteine, lysine, histidine, and arginine residues in critical regions of nuclear factors, proteases, and other proteins. Acrolein adduction disrupts the function of these biomacromolecules which may result in mutations, altered gene transcription, and modulation of apoptosis.

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Section: Glutathione Conjugation With Acroleinsupporting

confidence: 90%

Section: Glutathione Conjugation With Acroleinmentioning

confidence: 99%

Acrolein: Sources, metabolism, and biomolecular interactions relevant to human health and disease

Stevens

Maier

2008

Molecular Nutrition Food Res

615

634

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“…20 ILL of acrolein (0.30 mmo1) was added by micropipette. 1 H NMR results are in agreement with spectra published earlier [37,40] …”

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confidence: 92%

Fragmentation of protonated thioether conjugates of acrolein using low collision energies

Oberth

Jones

1997

J. Am. Soc. Mass Spectrom.

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The protonated mercapturic acid conjugate of acrolein, S-(3-oxopropyI)-N-acetyl-L-cysteine (I), undergoes facile retro-Michael loss of acrol ein in the gas phase. To determine whether extensive loss of acrolein would impede structural characterization of acrolein-peptide ad ducts, fragmentation reactions of a series of conjugates, formed by l,4-Michael addition of acrolein to peptides and cysteine derivatives, w ere investigated at collision cell potentials up to -50 V using a triple quadrupole mass spectrometer. Differences in fragmentation dynamics suggest protonation at the sulfur of the N-ac etylcysteine conjugate 1 facilitates retro-Michael elimination of acrolein with a low activation energy relative to other fragmentations. Analogous fragmentation was eliminated after borohydride reduction of the aldehyde to an alcohol. Retro-Michael fragmentation was not significant for acrolein conjugates of glutathione derivatives, suggesting that proton sequestration occurs in peptides with multiple amide linkages even when the peptide does not contain a basic amino group. An unexpected outcome of these experiments was the observation of a facile gas-phase cleavage of peptides on the N-terminal side of S-(3-oxopropylkysteine residues. Such fragmentation behavior may prove useful for locating cysteine residues in peptides. . Protein sulfhydryl groups are especially vulnerable to electrophiIic attack and form thioether conjugates whose presence indicates mechanisms of metabolic activation or detoxification. Knowledge of protein targets and sites of covalent attachment can be used to identify reactive metabolites, and these modified proteins can serve as biomarkers of exposure to xenobiotics in clinical and epidemiological studies [1][2][3][4][5][6][7][8]. One important class of xenobiotic-protein adducts forms via lA-Michael addition of a ,,B-unsaturated carbonyls to nucleophilic amino acid residues. Many a,,B-unsaturated carbonyls including acrylic monomers, combustion by-products or metabolites such as acrolein [1], and endogenous compounds such as 4-hydroxynonenal react with protein nucleophilic side chains via Michael addition [9][10][11].Mass spectrometry has emerged as a powerful analytical tool for the characterization of post-translationally modified peptides and proteins because this approach can identify the modifying group and sites of modification [12]. Earlier studies demonstrated the utility of fast atom bombardment mass spectrometry (FAB/MS) for identification of specific thioether conjuAddress reprint requests to Dr. A. Daniel Jones, Facility for Adv anced Instrumen tation, University of California, Dav is, CA 95616. E-mail: adjones@ucdavis.edu gates from biological samples [3,4,[13][14][15][16][17] . Using FAB or newer ionization techniques coupled with tandem mass spectrometry (MS/MS), researchers determined structures of thioether conjugates extracted from biological matrices [3][4][5][6][7][8][13][14][15][16][17][18][19][20][21][22]. In these MS/MS experiments, structural information was obtained fro...

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“…The results of Hashmi et al [13] on LLC-PK1 cells suggest that the mercapturic acids themselves could be cytotoxic. So far a noteworthy release of acrolein was only observed from mercapturic acids that have not been detected in vivo.…”

Section: Introductionmentioning

confidence: 97%

Toxicology and risk assessment of acrolein in food

Abraham

Andres

Palavinskas

et al. 2011

Molecular Nutrition Food Res

143

126

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Acrolein is an α,β-unsaturated aldehyde formed by thermal treatment of animal and vegetable fats, carbohydrates and amino acids. In addition it is generated endogenously. As an electrophile, acrolein forms adducts with gluthathione and other cellular components and is therefore cytotoxic. Mutagenicity was shown in some in vitro tests. Acrolein forms different DNA adducts in vivo, but mutagenic and cancerogenous effects have not been demonstrated for oral exposure. In subchronic oral studies, local lesions were detected in the stomach of rats. Systemic effects have not been reported from basic studies. A WHO working group established a tolerable oral acrolein intake of 7.5 μg/kg body weight/day. Acrolein exposure via food cannot be assessed due to analytical difficulties and the lack of reliable content measurements. Human biomonitoring of an acrolein urinary metabolite allows rough estimates of acrolein exposure in the range of a few μg/kg body weight/day. High exposure could be ten times higher after the consumption of certain foods. Although the estimation of the dietary acrolein exposure is associated with uncertainties, it is concluded that a health risk seems to be unlikely.

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Bioactivation mechanism of S-(3-oxopropyl)-N-acetyl-L-cysteine, the mercapturic acid of acrolein

Cited by 38 publications

References 28 publications

Acrolein: Sources, metabolism, and biomolecular interactions relevant to human health and disease

Acrolein: Sources, metabolism, and biomolecular interactions relevant to human health and disease

Fragmentation of protonated thioether conjugates of acrolein using low collision energies

Toxicology and risk assessment of acrolein in food

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