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An unexpected butadiene diolepoxide-mediated genotoxicity implies alternative mechanism for 1,3-butadiene carcinogenicity.

Authors
  • Nakamura, Jun1
  • Carro, Sujey2
  • Gold, Avram2
  • Zhang, Zhenfa3
  • 1 Laboratory of Laboratory Animal Science, Graduate School of Life and Environmental Biosciences, Osaka Prefecture University, Izumisano, Osaka, Japan; Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. Electronic address: [email protected] , (Japan)
  • 2 Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • 3 Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. Electronic address: [email protected]
Type
Published Article
Journal
Chemosphere
Publication Date
Mar 01, 2021
Volume
266
Pages
129149–129149
Identifiers
DOI: 10.1016/j.chemosphere.2020.129149
PMID: 33310515
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

1,3-Butadiene (BD) is abundant in combustion products such as cigarette smoke. While BD has been classified as a known human carcinogen, a long-standing question is the identity of the ultimate carcinogenic metabolite in humans. We hypothesize that 3,4-epoxybutane-1,2-diol (EBD) may play a critical role in human carcinogenesis due to its high bioavailability. We utilized a differential toxicity assay for BD metabolites and newly synthesized EBD analogs in a series of isogenic chicken cells lacking specific DNA repair proteins to address the mode of action of BD genotoxicity and infer a mode of action. Surprisingly, as with the diepoxide 1,2:3,4-diepoxybutane (DEB), the monoepoxide EBD showed remarkable toxicity to cells deficient in Fanconi anemia (FANC) genes. This observation suggests that EBD may be transformed into a bifunctional metabolite and forms interstrand cross-links. EBD and its analog with a hydroxy substituent at C1 were found to be highly toxic to FANCD2-deficient chicken and human cells. The Results suggest that EBD may be transformed to a bifunctional epoxy aldehyde, perhaps by alcohol dehydrogenase, to which the observed FANC sensitivity could be attributed. The implications of this study are very important in considering mechanisms by which EBD may cause leukemia and lymphoma in humans exposed to BD. Copyright © 2020 Elsevier Ltd. All rights reserved.

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