Journal Article

Identification and Pathway Mapping of Furan Target Proteins Reveal Mitochondrial Energy Production and Redox Regulation as Critical Targets of Furan Toxicity

Sabrina Moro, J. Kevin Chipman, Philipp Antczak, Nil Turan, Wolfgang Dekant, Francesco Falciani and Angela Mally

in Toxicological Sciences

Volume 126, issue 2, pages 336-352
Published in print April 2012 | ISSN: 1096-6080
Published online January 2012 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/kfs005
Identification and Pathway Mapping of Furan Target Proteins Reveal Mitochondrial Energy Production and Redox Regulation as Critical Targets of Furan Toxicity

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Furan, a heat-generated food contaminant, is hepatotoxic and carcinogenic in rodents. Furan is oxidized by cytochrome P450 2E1 to cis-2-butene-1,4-dial, a chemically reactive α,β-unsaturated dialdehyde, which has been identified as the key toxic metabolite of furan based on its ability to interact with tissue nucleophiles. In addition to genotoxicity, sustained cytotoxicity mediated through covalent binding of cis-2-butene-1,4-dial to critical target proteins is thought to play a key role in furan carcinogenicity. To identify putative protein targets of reactive furan metabolites, male F344/N rats (n = 5 per dose) were administered a single dose of [3,4-14C]-furan (20 mCi/mmol) at doses associated with hepatotoxicity following long-term exposure (0.1 and 2 mg/kg body weight [bw]). Liver proteins were separated by two-dimensional gel electrophoresis and protein spots carrying radiolabel were located by fluorography. In total, 83 discrete protein spots containing 14C were consistently detected in livers of animals given [3,4-14C]-furan at 2.0 mg/kg bw, accounting for 4–5% of the proteome covered by our analyses. Protein spots were excised and digested in gel with trypsin for identification by protein mass spectrometry. Protein database search and subsequent pathway mapping identified 61 proteins localized predominantly in the cytosol and mitochondria, including structural proteins, mitochondrial enzymes involved in glucose metabolism, mitochondrial β-oxidation, and adenosine triphosphate synthesis, and proteins that participate in the maintenance of redox homeostasis and protein folding. Collectively, our data suggest that functional loss of several individual proteins and interference with pathways, most notably mitochondrial energy production, redox regulation, and protein folding, may combine to disrupt cell homeostasis and cause hepatocyte cell death.

Keywords: furan; protein adducts; liver; carcinogenicity

Journal Article.  11127 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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