1,3-Butadiene-Induced Adenine DNA Adducts Are Genotoxic but Only Weakly Mutagenic When Replicated in Escherichia coli of Various Repair and Replication Backgrounds.

Citation data:

Chemical research in toxicology, ISSN: 1520-5010, Vol: 30, Issue: 5, Page: 1230-1239

Publication Year:
2017
Usage 5
Abstract Views 5
Captures 5
Readers 3
Exports-Saves 2
Citations 1
Citation Indexes 1
PMID:
28394575
DOI:
10.1021/acs.chemrestox.7b00064
Author(s):
Chang, Shiou-Chi, Seneviratne, Uthpala I, Wu, Jie, Tretyakova, Natalia, Essigmann, John M
Publisher(s):
American Chemical Society (ACS)
Tags:
Pharmacology, Toxicology and Pharmaceutics
article description
The adverse effects of the human carcinogen 1,3-butadiene (BD) are believed to be mediated by its DNA-reactive metabolites such as 3,4-epoxybut-1-ene (EB) and 1,2,3,4-diepoxybutane (DEB). The specific DNA adducts responsible for toxic and mutagenic effects of BD, however, have yet to be identified. Recent in vitro polymerase bypass studies of BD-induced adenine (BD-dA) adducts show that DEB-induced N,N-DHB-dA (DHB = 2,3-dihydroxybutan-1,4-diyl) and 1,N-γ-HMHP-dA (HMHP = 2-hydroxy-3-hydroxymethylpropan-1,3-diyl) adducts block replicative DNA polymerases but are bypassed by human polymerases η and κ, leading to point mutations and deletions. In contrast, EB-induced N-HB-dA (HB = 2-hydroxy-3-buten-1-yl) does not block DNA synthesis and is nonmutagenic. In the present study, we employed a newly established in vivo lesion-induced mutagenesis/genotoxicity assay via next-generation sequencing to evaluate the in vivo biological consequences of S-N-HB-dA, R,R-N,N-DHB-dA, S,S-N,N-DHB-dA, and R,S-1,N-γ-HMHP-dA. In addition, the effects of AlkB-mediated direct reversal repair, MutM and MutY catalyzed base excision repair, and DinB translesion synthesis on the BD-dA adducts in bacterial cells were investigated. BD-dA adducts showed the expected inhibition of DNA replication in vivo but were not substantively mutagenic in any of the genetic environments investigated. This result is in contrast with previous in vitro observations and opens the possibility that E. coli repair and bypass systems other than the ones studied here are able to minimize the mutagenic properties of BD-dA adducts.

This article has 0 Wikipedia mention.