Identification of N alpha-acetyl-epsilon-(2-propenal)lysine as a urinary metabolite of malondialdehyde.

McGirr, Larry G.; Hadley, M.; Draper, H. H.

doi:10.1016/s0021-9258(17)36271-3

Cited by 72 publications

(22 citation statements)

References 24 publications

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“…The observation of 10 as a hepatocyte metabolite suggests that 7a undergoes N-acetylation in a reaction likely catalyzed by an N-acetyltransferase (28,29). A similar biotransformation has been reported for malondialdehyde-lysine reaction products, where N R -acetyl-ε-(2-propenal)lysine was detected in urine from malondialdehyde-treated rats (30). The mercapturic acid pathway is responsible for the formation of 6a from 7a.…”

Section: Discussionsupporting

confidence: 58%

Degraded Protein Adducts of cis-2-Butene-1,4-dial Are Urinary and Hepatocyte Metabolites of Furan

Ding

Sullivan

Phillips

et al. 2009

Chem. Res. Toxicol.

131

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Furan is a liver toxicant and carcinogen in rodents. Based on these observations and the large potential for human exposure, furan has been classified as a possible human carcinogen. The mechanism of tumor induction by furan is unknown. However, the toxicity requires cytochrome P450 catalyzed oxidation of furan. The product of this oxidation, cis-2-butene-1,4-dial (BDA), reacts readily with glutathione, amino acids and DNA and is a bacterial mutagen in Ames assay strain TA104. Characterization of the urinary metabolites of furan is expected to provide information regarding the structure(s) of the reactive metabolite(s). Recently, several urinary metabolites have been identified. We reported the presence of a mono-glutathione-BDA reaction product,Three additional urinary metabolites of furan were also characterized:and its sulfoxide. It was postulated that these three metabolites are derived from degraded protein adducts. However, the possibility that these metabolites result from reaction of BDA with free lysine and/or cysteine was not ruled out. In this latter case, one might predict that the reaction of thiol-BDA with free lysine would not occur exclusively on the ε-amino group. Reaction of BDA with Nacetylcysteine or GSH in the presence of lysine indicated that both the α-and ε-amino groups of lysine can be modified by thiol-BDA. The N-acetylcysteine-BDA-N-acetyllysine urinary metabolites were solely linked through the ε-amino group of lysine. A GSH-BDA-lysine crosslink was a significant hepatocyte metabolite of furan. In this case, the major product resulted from reaction with the ε-amino group of lysine, however, small amounts of the α-amino reaction product were also observed. Western analysis of liver and hepatocyte protein extracts using anti-GSH antibody indicated that GSH was covalently linked to proteins in tissues or cells exposed to furan. Our data support the hypothesis that GSH-BDA can react with either free lysine or protein lysine groups. These data suggest that there are multiple pathways by which furan can modify cellular nucleophiles. In one pathway, BDA reacts directly with proteins to form cysteine-lysine reaction products. In another, BDA reacts with GSH to form GSH-BDA conjugates which then reacts with cellular nucleophiles like free lysine or lysine moieties in proteins. Both pathways will give rise to N-acetyl-S- [1-(5-acetylamino-5-carboxypentyl)-1H-pyrrol-3-yl]-L-cysteine. Given the abundance of these metabolites in urine of furan-treated rats, these pathways appear to be major pathways of furan biotransformation in vivo.

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Section: Discussionsupporting

confidence: 58%

Degraded Protein Adducts of cis-2-Butene-1,4-dial Are Urinary and Hepatocyte Metabolites of Furan

Ding

Sullivan

Phillips

et al. 2009

Chem. Res. Toxicol.

131

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“…The nitrogen atom is derived from the side chain amino group of lysine in three cases ( II , III , and IV ) and from the amino terminal of glutamic acid in glutathione ( I and V ). Lysine adducts and their N -acetylated derivatives had already been discussed as biomarkers in the context of malondialdehyde , and of the dialdehyde formed in the metabolism of aflatoxin B 1 , .…”

Section: Discussionmentioning

confidence: 99%

Biomarkers of Furan Exposure by Metabolic Profiling of Rat Urine with Liquid Chromatography-Tandem Mass Spectrometry and Principal Component Analysis

Kellert

Wagner

Lutz

et al. 2008

Chem. Res. Toxicol.

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Furan has been found in a number of heated food items and is carcinogenic in the liver of rats and mice. Estimates of human exposure on the basis of concentrations measured in food are not reliable because of the volatility of furan. A biomarker approach is therefore indicated. We searched for metabolites excreted in the urine of male Fischer 344 rats treated by oral gavage with 40 mg of furan per kg of body weight. A control group received the vehicle oil only. Urine collected over two 24-h periods both before and after treatment was analyzed by a column-switching LC-MS/MS method. Data were acquired by a full scan survey scan in combination with information dependent acquisition of fragmentation spectra by the use of a linear ion trap. Areas of 449 peaks were extracted from the chromatograms and used for principal component analysis (PCA). The first principal component fully separated the samples of treated rats from the controls in the first post-treatment sampling period. Thirteen potential biomarkers selected from the corresponding loadings plot were reanalyzed using specific transitions in the MRM mode. Seven peaks that increased significantly upon treatment were further investigated as biomarkers of exposure. MS/MS information indicated conjugation with glutathione on the basis of the characteristic neutral loss of 129 for mercapturates. Adducts with the side chain amino group of lysine were characterized by a neutral loss of 171 for N-acetyl- l-lysine. Analysis of products of in vitro incubations of the reactive furan metabolite cis-2-butene-1,4-dial with the respective amino acid derivatives supported five structures, including a new 3-methylthio-pyrrole metabolite probably formed by beta-lyase reaction on a glutathione conjugate, followed by methylation of the thiol group. Our results demonstrate the potential of comprehensive mass spectrometric analysis of urine combined with multivariate analyses for metabolic profiling in search of biomarkers of exposure.

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“…Some researchers attempted to detect MDA using liquid chromatography-mass spectrometry (LC-MS) and gas chromatography-mass spectrometry (GC-MS), which showed to be more specific and sensitive than TBARS analysis, as well as effective for both free and adducted MDA (200,201). Except in blood investigations, amino acid adducts of MDA, such as Nepsilon-(2-propenal) lysine, N-α-acetyl-(epsilon)-(2-propenal) lysine, N-(2-propenal) serine, and N-(2-propenal) ethanolamine (202)(203)(204)(205) have been found in urine by mass spectrometry. 4-HNE is also a lipid peroxidation end product and one of the most cytotoxic products.…”

Section: Mda and 4-hydroxynonenalmentioning

confidence: 99%

Oxidative Stress in Autism Spectrum Disorder—Current Progress of Mechanisms and Biomarkers

et al. 2022

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Autism spectrum disorder (ASD) is a type of neurodevelopmental disorder that has been diagnosed in an increasing number of children around the world. Existing data suggest that early diagnosis and intervention can improve ASD outcomes. However, the causes of ASD remain complex and unclear, and there are currently no clinical biomarkers for autism spectrum disorder. More mechanisms and biomarkers of autism have been found with the development of advanced technology such as mass spectrometry. Many recent studies have found a link between ASD and elevated oxidative stress, which may play a role in its development. ASD is caused by oxidative stress in several ways, including protein post-translational changes (e.g., carbonylation), abnormal metabolism (e.g., lipid peroxidation), and toxic buildup [e.g., reactive oxygen species (ROS)]. To detect elevated oxidative stress in ASD, various biomarkers have been developed and employed. This article summarizes recent studies about the mechanisms and biomarkers of oxidative stress. Potential biomarkers identified in this study could be used for early diagnosis and evaluation of ASD intervention, as well as to inform and target ASD pharmacological or nutritional treatment interventions.

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Identification of N alpha-acetyl-epsilon-(2-propenal)lysine as a urinary metabolite of malondialdehyde.

Cited by 72 publications

References 24 publications

Degraded Protein Adducts of cis-2-Butene-1,4-dial Are Urinary and Hepatocyte Metabolites of Furan

Degraded Protein Adducts of cis-2-Butene-1,4-dial Are Urinary and Hepatocyte Metabolites of Furan

Biomarkers of Furan Exposure by Metabolic Profiling of Rat Urine with Liquid Chromatography-Tandem Mass Spectrometry and Principal Component Analysis

Oxidative Stress in Autism Spectrum Disorder—Current Progress of Mechanisms and Biomarkers

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