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Title: Cytotoxicity, genotoxicity, and mutagenicity of 1-chloro-2-hydroxy-3-butene and 1-chloro-3-buten-2-one, two alternative metabolites of 1,3-butadiene

The cytotoxicity, genotoxicity, and mutagenicity of 1-chloro-2-hydroxy-3-butene (CHB), a known in vitro metabolite of the human carcinogen 1,3-butadiene, have not previously been investigated. Because CHB can be bioactivated by alcohol dehydrogenases to yield 1-chloro-3-buten-2-one (CBO), a bifunctional alkylating agent that caused globin-chain cross-links in erythrocytes, in the present study we investigated the cytotoxic and genotoxic potential of CHB and CBO in human normal hepatocyte L02 cells using the MTT assay, the relative cloning efficiency assay and the comet assay. We also investigated the mutagenic potential of these compounds with the Ames test using Salmonella strains TA1535 and TA1537. The results provide clear evidence for CHB and CBO being both cytotoxic and genotoxic with CBO being approximately 100-fold more potent than CHB. Interestingly, CHB generated both single-strand breaks and alkali-labile sites on DNA, whereas CBO produced only alkali-labile sites. CHB did not directly result in DNA breaks, whereas CBO was capable of directly generating breaks on DNA. Interestingly, both compounds did not induce DNA cross-links as examined by the comet assay. The Ames test results showed that CHB induced point mutation but not frameshift mutation, whereas the toxic effects of CBO made it difficult to reliably assess the mutagenic potential ofmore » CBO in the two strains. Collectively, the results suggest that CHB and CBO may play a role in the mutagenicity and carcinogenicity of 1,3-butadiene. - Highlights: • 1-Chloro-2-hydroxy-3-butene (CHB) is cytotoxic and genotoxic in human liver cells. • The CHB metabolite, 1-chloro-3-buten-2-one (CBO) is ∼ 100-fold more toxic than CHB. • CHB and CBO cause DNA alkali-labile sites, but only CBO directly causes DNA breaks. • CHB is mutagenic in the Ames test, but CBO is too toxic in the assay. • The results suggest a role for CHB in 1,3-butadiene genotoxicity and mutagenicity.« less
Authors:
; ; ;  [1] ;  [1] ;  [2] ;  [3]
  1. Institute of Environmental Pollution and Health, School of Environmental and Chemical Engineering, Shanghai University, Shanghai 200444 (China)
  2. Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, WI 53706 (United States)
  3. (United States)
Publication Date:
OSTI Identifier:
22285353
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 271; Journal Issue: 1; Other Information: Copyright (c) 2013 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; BUTADIENE; BUTENES; CARCINOGENS; CLONING; DNA; ERYTHROCYTES; GENE MUTATIONS; LIVER CELLS; METABOLITES; MUTAGEN SCREENING; STRAND BREAKS; TOXICITY