Publication Type Journal Article
Title New insights into the molecular mechanisms of chemical carcinogenesis: In vivo adduction of histone H2B by a reactive metabolite of the chemical carcinogen furan
Authors João Pedro da Costa Nunes Inês Sofia Lança Martins Catarina Sofia Romão Charneira Igor P. Pogribny Aline de Conti Frederick A. Beland M. Matilde Marques Cristina C. Jacob Alexandra Maria Moita Antunes
Groups BioMol
Journal TOXICOLOGY LETTERS
Year 2016
Month December
Volume 264
Number
Pages 106-113
Abstract Furan is a rodent hepatocarcinogen ubiquitously found in the environment and heat-processed foods. Furan undergoes cytochrome P450 2E1-catalyzed bioactivation to cis-2-butene-1,4-dial (BDA), which has been shown to form an electrophilic conjugate (GSH-BDA) with glutathione. Both BDA and GSH-BDA yield covalent adducts with lysine residues in proteins. Dose-and time-dependent epigenetic histone alterations have been observed in furan-treated rats. While the covalent modification of histones by chemical carcinogens has long been proposed, histone-carcinogen adducts have eluded detection in vivo. In this study, we investigated if the covalent modification of histones by furan may occur in vivo prior to epigenetic histone alterations. Using a bottom-up methodology, involving the analysis of tryptic peptides by liquid chromatography-high resolution mass spectrometry, we obtained evidence for a cross-link between GSH-BDA and lysine 107 of histone H2B isolated from the livers of male F344 rats treated with tumorigenic doses of furan. This cross-link was detected at the shortest treatment period (90 days) in the lowest dose group (0.92 mg/kg body weight/day), prior to the identification of epigenetic changes, and occurred at a lysine residue that is a target for epigenetic modifications and crucial for nucleosome stability. Our results represent the first unequivocal proof of the occurrence of carcinogen-modified histones in vivo and suggest that such modification happens at the initial stages of furan-induced carcinogenesis. This type of alteration may be general in scope, opening new insights into the mechanisms of chemical carcinogenesis/toxicity and new opportunities for the development of early compound-specific biomarkers of exposure. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
DOI http://dx.doi.org/10.1016/j.toxlet.2016.10.018
ISBN
Publisher
Book Title
ISSN 0378-4274
EISSN 1879-3169
Conference Name
Bibtex ID ISI:000390489200012
Observations
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