{"title":"Formation of the toxic furan metabolite 2-butene-1,4-dial through hemin-induced degradation of 2,4-alkadienals in fried foods.","authors":"Hiroshi Kasai, Kazuaki Kawai, Koichi Fujisawa","doi":"10.1186/s41021-025-00330-2","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>The mechanism of protein modification by 2,4-alkadienals (ADE), lipid peroxidation products prevalent in fried foods, was investigated through model reactions.</p><p><strong>Results: </strong>A mixture of 2,4-heptadienal (HDE) and hemin was initially incubated at pH 3.0-7.4, followed by treatment with acetyl-cysteine (AcCys) and acetyl-lysine (AcLys) at pH 7.4. Analysis via HPLC revealed a product with a characteristic UV spectrum as the primary peak. This product was identified as an AcCys-pyrrole-AcLys (CPL) crosslink derived from AcCys, 2-butene-1,4-dial (BDA), and AcLys. Increasing the HDE concentration in the initial reaction led to maximum CPL formation at pH 3.5 in the presence of hemin. Lowering the HDE concentration with a higher Cys/HDE ratio resulted in CPL formation, which was observed at pH 7.4 and 3.5 in the presence of hemin. Upon incubation of ADE and hemin at pH 3.0-3.5, BDA was directly identified as 2,4-dinitrophenylhydrazone. BDA was also detected in the 2,4-decadienal reaction mixture. Additionally, a notable propensity for high BDA-dC adduct formation with hemin under acidic conditions was observed, consistent with the results of CPL assay and BDA-2,4-dinitrophenylhydrazone analysis.</p><p><strong>Conclusions: </strong>1) BDA is efficiently generated from ADE in the presence of hemin under gastric conditions, and 2) BDA-derived CPL can also form under physiological conditions (pH 7.4) through the interaction of ADE, hemin, Cys, and Lys. BDA is recognized as the primary reactive metabolite of the suspected carcinogen furan (IARC, 2B). Given that human intake of ADE exceeds that of furan and acrylamide (IARC 2A) by several orders of magnitude, and the estimated hemin concentration in the stomach post-meal is comparable to the present study, a substantial amount of BDA may form in the stomach following consumption of fried foods and meat. The risk assessment of ADE warrants a thorough re-evaluation, based on the toxicity mechanism of BDA.</p>","PeriodicalId":12709,"journal":{"name":"Genes and Environment","volume":"47 1","pages":"8"},"PeriodicalIF":2.7000,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Genes and Environment","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s41021-025-00330-2","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"GENETICS & HEREDITY","Score":null,"Total":0}
引用次数: 0
Abstract
Background: The mechanism of protein modification by 2,4-alkadienals (ADE), lipid peroxidation products prevalent in fried foods, was investigated through model reactions.
Results: A mixture of 2,4-heptadienal (HDE) and hemin was initially incubated at pH 3.0-7.4, followed by treatment with acetyl-cysteine (AcCys) and acetyl-lysine (AcLys) at pH 7.4. Analysis via HPLC revealed a product with a characteristic UV spectrum as the primary peak. This product was identified as an AcCys-pyrrole-AcLys (CPL) crosslink derived from AcCys, 2-butene-1,4-dial (BDA), and AcLys. Increasing the HDE concentration in the initial reaction led to maximum CPL formation at pH 3.5 in the presence of hemin. Lowering the HDE concentration with a higher Cys/HDE ratio resulted in CPL formation, which was observed at pH 7.4 and 3.5 in the presence of hemin. Upon incubation of ADE and hemin at pH 3.0-3.5, BDA was directly identified as 2,4-dinitrophenylhydrazone. BDA was also detected in the 2,4-decadienal reaction mixture. Additionally, a notable propensity for high BDA-dC adduct formation with hemin under acidic conditions was observed, consistent with the results of CPL assay and BDA-2,4-dinitrophenylhydrazone analysis.
Conclusions: 1) BDA is efficiently generated from ADE in the presence of hemin under gastric conditions, and 2) BDA-derived CPL can also form under physiological conditions (pH 7.4) through the interaction of ADE, hemin, Cys, and Lys. BDA is recognized as the primary reactive metabolite of the suspected carcinogen furan (IARC, 2B). Given that human intake of ADE exceeds that of furan and acrylamide (IARC 2A) by several orders of magnitude, and the estimated hemin concentration in the stomach post-meal is comparable to the present study, a substantial amount of BDA may form in the stomach following consumption of fried foods and meat. The risk assessment of ADE warrants a thorough re-evaluation, based on the toxicity mechanism of BDA.
期刊介绍：
Genes and Environment is an open access, peer-reviewed journal that aims to accelerate communications among global scientists working in the field of genes and environment. The journal publishes articles across a broad range of topics including environmental mutagenesis and carcinogenesis, environmental genomics and epigenetics, molecular epidemiology, genetic toxicology and regulatory sciences.
Topics published in the journal include, but are not limited to, mutagenesis and anti-mutagenesis in bacteria; genotoxicity in mammalian somatic cells; genotoxicity in germ cells; replication and repair; DNA damage; metabolic activation and inactivation; water and air pollution; ROS, NO and photoactivation; pharmaceuticals and anticancer agents; radiation; endocrine disrupters; indirect mutagenesis; threshold; new techniques for environmental mutagenesis studies; DNA methylation (enzymatic); structure activity relationship; chemoprevention of cancer; regulatory science. Genetic toxicology including risk evaluation for human health, validation studies on testing methods and subjects of guidelines for regulation of chemicals are also within its scope.
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