Mutational spectrum of 1,3-butadiene and metabolites 1,2-epoxybutene and 1,2,3,4-diepoxybutane to assess mutagenic mechanisms

Recio, Leslie; Steen, Ann-Marie; Pluta, Linda; Meyer, Kathy G.; Saranko, Christopher J.

doi:10.1016/s0009-2797(01)00220-4

Cited by 57 publications

(81 citation statements)

References 31 publications

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“…Cellular physiology (e.g., temporal transcriptional profiling) was not measured in this study, and it is possible that stress responses are rapidly activated, producing the complement of machinery required for the processing of BDO 2 -induced lesions. Our results, however, provide a possible explanation for the earlier discovery that the mutational spectra observed in molecular analyses of BD-associated mutagenicity, in both humans and mice, show a shift towards deletion mutants when compared to the spontaneous spectrum Meng et al, 2000;Recio et al, 2001). Finally, the correlation between acutely induced genomic damage and the induction of Hprt mutants might indicate that a substantial number of lesions occurring within the Hprt gene itself are improperly repaired.…”

Section: Discussionmentioning

confidence: 51%

“…The mutagenicity and carcinogenicity of BD have also been demonstrated in laboratory mice (Huff et al, 1985;Cochrane and Skopek, 1994;Meng et al, 1998aMeng et al, , 1999a. More recently, research has focused on elucidating the biotransformation of BD and its mutational characteristics (Meng et al, 2000;Recio et al, 2001). Biotransformation studies suggest that mutagenicity is governed by a balance between the oxidation of BD by monooxygenases (CYP450s) to electrophilic epoxides and the hydrolytic detoxification of these epoxides by microsomal epoxide hydrolase (mEH) (summarized in Jackson et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

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A model of sensitivity: 1,3‐butadiene increases mutant frequencies and genomic damage in mice lacking a functional microsomal epoxide hydrolase gene

Wickliffe

Ammenheuser

Salazar

et al. 2003

Environ and Mol Mutagen

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The specific role that polymorphisms in xenobiotic metabolizing enzymes play in modulating sensitivity to 1,3-butadiene (BD) genotoxicity has been relatively unexplored. The enzyme microsomal epoxide hydrolase (mEH) is important in detoxifying the mutagenic epoxides of BD (butadiene monoepoxide [BDO], butadiene diepoxide [BDO(2)]). Polymorphisms in the human mEH gene appear to affect the function of the enzyme. We exposed mice with normal mEH activity (WT) and knockout mice without mEH activity (KO) to 20 ppm BD (inhalation) or 30 mg/kg BDO(2) (intraperitoneal [IP] injection). We then compared Hprt mutant frequencies (MFs) among these groups. KO mice exposed to BD exhibited a significant (P < 0.05) 12.4-fold increase in MF over controls and a significant 5.4-fold increase in MF over exposed WT mice. Additionally, KO mice exposed to BDO(2) exhibited a significant 4.5-fold increase in MF over controls and a significant 1.7-fold increase in MF over exposed WT mice. We also compared genomic damage in WT and KO mice (comet tail moment) following IP exposure to 3 mg/kg and 30 mg/kg BDO(2). KO mice exposed to 3 mg/kg exhibited significantly more DNA damage than controls (7.5-12.1-fold increase) and exposed WT mice (3 mg/kg; 4.8-fold increase). KO mice exposed to 30 mg/kg BDO(2) exhibited significantly more DNA damage than all other groups (2.3-27.9-fold increase). Correlation analysis indicated that a significant, positive relationship (r(2) = 0.92) exists between comet-measured damage and Hprt MFs. The lack of mEH activity increases the genetic sensitivity of mice exposed to BD and BDO(2). This model should facilitate a mechanistic understanding of the observed variation in human genetic sensitivity following exposure to BD.

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Section: Discussionmentioning

confidence: 51%

Section: Introductionmentioning

confidence: 99%

A model of sensitivity: 1,3‐butadiene increases mutant frequencies and genomic damage in mice lacking a functional microsomal epoxide hydrolase gene

Wickliffe

Ammenheuser

Salazar

et al. 2003

Environ and Mol Mutagen

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“…GC?TA mutations are also the predominant ones observed in studies of mutagenesis by N 2 -deoxyguanosine adducts of 1,3-butadiene (Carmical et al, 2000), adducts of 4-aminobiphenyl (Melchior et al, 1994), and 8-oxodeoxyguanosine (Moriya, 1993). Other studies of butadiene mutagenesis demonstrate the occurrence of GC?AT, AT?TA, and GC?TA mutations (Recio et al, 2000). Products of the further oxidation of 8-oxodeoxyguanosine by peroxynitrite are highly efficient in producing GC?TA mutations (Henderson et al, 2002).…”

Section: Likely Mutationsmentioning

confidence: 97%

Tobacco smoke carcinogens, DNA damage and p53 mutations in smoking-associated cancers

et al. 2002

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It is estimated that cigarette smoking kills over 1 000 000 people each year by causing lung cancer as well as many other neoplasmas. p53 mutations are frequent in tobaccorelated cancers and the mutation load is often higher in cancers from smokers than from nonsmokers. In lung cancers, the p53 mutational patterns are different between smokers and nonsmokers with an excess of G to T transversions in smoking-associated cancers. The prevalence of G to T transversions is 30% in smokers' lung cancer but only 12% in lung cancers of nonsmokers. A similar trend exists, albeit less marked, in laryngeal cancers and in head and neck cancers. This type of mutation is infrequent in most other tumors aside from hepatocellular carcinoma. At several p53 mutational hotspots common to all cancers, such as codons 248 and 273, a large fraction of the mutations are G to T events in lung cancers but are almost exclusively G to A transitions in non-tobacco-related cancers. Two important classes of tobacco smoke carcinogens are the polycyclic aromatic hydrocarbons (PAH) and the nicotine-derived nitrosamines. Recent studies have indicated that there is a strong coincidence of G to T transversion hotspots in lung cancers and sites of preferential formation of PAH adducts along the p53 gene. Endogenously methylated CpG dinucleotides are the preferred sites for G to T transversions, accounting for more than 50% of such mutations in lung tumors. The same dinucleotide, when present within CpGmethylated mutational reporter genes, is the target of G to T transversion hotspots in cells exposed to the model PAH compound benzo[a]pyrene-7,8-diol-9,10-epoxide. As summarized here, a number of other tobacco smoke carcinogens also can cause G to T transversion mutations. The available data suggest that p53 mutations in lung cancers can be attributed to direct DNA damage from cigarette smoke carcinogens rather than to selection of pre-existing endogenous mutations.

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“…106-99-0) is a colorless gas regularly used in the production of plastics, thermoplastic resins, and styrene-butadiene rubber. Also, it is produced by incomplete combustion of motor fuels or by tobacco smoking [Recio et al, 2001;US-EPA, 2002]. Styrene-butadiene rubber workers have an increased mortality risk of leukemia [Kirman et al, 2010].…”

Section: Introductionmentioning

confidence: 99%

“…After being absorbed (mainly through the respiratory system) and metabolized by several enzymes such as CYP2E1, CY-P2A6, CYP2C9, CYP3A4, epoxide hydrolase and glutathione transferases, 1,3-butadiene is oxidized to 1,2-epoxy 3-butene [Seaton et al, 1995;Krause and Elfarra, 1997;Abdel-Rahman et al, 2001;US-EPA, 2002]. A second oxidation renders 1,2: 3,4-diepoxybutane (DEB), which has the highest genotoxic potency of all metabolites of 1,3-butadiene [Seaton et al, 1995;Krause and Elfarra, 1997;Abdel-Rahman et al, 2001;Recio et al, 2001;US-EPA, 2002;Kirman et al, 2010]. The genotoxic potential of any chemical considers its ability to induce structural mutations (clastogenic activity) and/or aneuploidy (aneugenic activity) [Parry et al, 2002].…”

Section: Introductionmentioning

confidence: 99%

1,2:3,4-Diepoxybutane Induces Multipolar Mitosis in Cultured Human Lymphocytes

Torres¹,

Cruz²,

Gutiérrez³

et al. 2016

Cytogenet Genome Res

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1,3-Butadiene, a colorless gas regularly used in the production of plastics, thermoplastic resins, and styrene-butadiene rubber, poses an increased leukemia mortality risk to workers in this field. 1,3-Butadiene is also produced by incomplete combustion of motor fuels or by tobacco smoking. It is absorbed principally through the respiratory system and metabolized by several enzymes rendering 1,2:3,4-diepoxybutane (DEB), which has the highest genotoxic potency of all metabolites of 1,3-butadiene. DEB is considered a carcinogen mainly due to its high potential as clastogen, which induces structural chromosome aberrations such as sister chromatid exchanges, chromosomal breaks, and micronuclei. Due to its clastogenic effect, DEB is one of the most used agents for diagnostic studies of Fanconi anemia, a recessively inherited disease related to mutations affecting several genes involved in a common DNA repair pathway. When performing Fanconi anemia diagnostic tests in our laboratory, we have observed occasional multipolar mitosis (MM) in lymphocyte cultures exposed to 0.1 μg/ml of DEB and harvested in the absence of any mitotic spindle inhibitor. Although previous studies reported an aneugenic effect (i.e. it induces aneuploidy) of DEB, no mechanism was suggested to explain such observations. Therefore, the aim of this study was to investigate whether exposure to 0.1 μg/ml of DEB is significantly associated with the occurrence of MM. We blindly assessed the frequency of MM in lymphocyte cultures from 10 nonsmoking healthy individuals. Two series of 3 cultures were performed from each sample under different conditions: A, without DEB; B, with 0.1 μg/ml of DEB, and C, with 25 μM of mitomycin C as positive control. Cultures exposed to DEB showed higher frequencies of MM (23 of 2,000 cells) than did the unexposed ones (3 of 2,000 cells).

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Mutational spectrum of 1,3-butadiene and metabolites 1,2-epoxybutene and 1,2,3,4-diepoxybutane to assess mutagenic mechanisms

Cited by 57 publications

References 31 publications

A model of sensitivity: 1,3‐butadiene increases mutant frequencies and genomic damage in mice lacking a functional microsomal epoxide hydrolase gene

A model of sensitivity: 1,3‐butadiene increases mutant frequencies and genomic damage in mice lacking a functional microsomal epoxide hydrolase gene

Tobacco smoke carcinogens, DNA damage and p53 mutations in smoking-associated cancers

1,2:3,4-Diepoxybutane Induces Multipolar Mitosis in Cultured Human Lymphocytes

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