Disease relevance of Epoxybutene

• The influence of 3,4-epoxybutene (EB), the primary metabolite of 1,3-butadiene, on the colony-forming response of hematopoietic progenitor cells (HPCs) from C57BL/6, Sl, and W mice was investigated in order to elucidate the role of altered HPC regulation in the pathogenesis of 1,3-butadiene toxicity [1].
• In the lower concentration range where first order metabolism applies (up to about 500 ppm) epoxybutene is metabolized by mice at higher rates compared to rats (metabolic clearance per kg body weight, mice: 24,900 ml X h-1, rats: 13,400 ml X h-1) [2].

High impact information on Epoxybutene

• Experiments conducted with cells from Sl and W mice revealed that they lack the same primitive HPC targeted by EB [1].
• 1,3-Butadiene was oxidized by human myeloperoxidase in the absence of KCl to yield butadiene monoxide (BM) and crotonaldehyde (CA), but at KCl concentrations higher than 50 mM, 1-chloro-2-hydroxy-3-butene (CHB) was the major metabolite detected; metabolite formation was dependent on incubation time, pH, KCl, 1,3-butadiene, and H2O2 concentrations [3].
• Palladium catalyzed asymmetric allylic alkylation reaction of an amine with two equivalents of butadiene monoxide allows for the expedient synthesis of trans- and cis-2,5-dihydropyrroles [4].
• The solution structure of the N1-(1-hydroxy-3-buten-2(S)-yl)-2'-deoxyinosine adduct arising from the alkylation of adenine N1 by butadiene epoxide (BDO), followed by deamination to deoxyinosine, was determined, in the oligodeoxynucleotide d(CGGACXAGAAG).d(CTTCTCGTCCG) [5].
• Structure of an oligodeoxynucleotide containing a butadiene oxide-derived N1 beta-hydroxyalkyl deoxyinosine adduct in the human N-ras codon 61 sequence [5].

Biological context of Epoxybutene

• EB pretreatment in vitro and butadiene exposure in vivo mimic hematopoietic defects seen in W and Sl mice, suggesting that the pleotypic pathologies encountered in these murine models may be largely due to a common defect in primitive HPCs [1].
• It predicts that inhalation uptake of butadiene and formation and retention of epoxybutene are controlled to a much greater extent by physiological parameters than by biochemical parameters and that storage in the fat represents a significant fraction of the retained butadiene [6].
• Induction of sister chromatid exchange by 1,2-epoxy-3-butene in cultured human lymphocytes: influence of GSTT1 genotype [7].
• The same two compounds I and II in a similar (54:46) ratio have been identified after acidic or thermal hydrolysis of DNA which had been reacted with 3,4-epoxy-1-butene under similar conditions [8].
• If formed in sufficient amounts, DEB and MEB may produce chromosome damage of the type found in leukemia following exposure to butadiene [9].

Anatomical context of Epoxybutene

• To test for other types of genotoxicity, the micronucleus assay and fluorescence in situ hybridization (FISH) have been used to detect chromosome damage in human lymphocytes caused by two reactive metabolites of butadiene, diepoxybutane (DEB) and monoepoxybutene (MEB) [9].
• Oxidation of 1,2-epoxy-3-butene to 1,2:3,4-diepoxybutane by cDNA-expressed human cytochromes P450 2E1 and 3A4 and human, mouse and rat liver microsomes [10].
• Identification and quantitation of DNA adducts from calf thymus DNA exposed to 3,4-epoxy-1-butene [11].
• Mutagenicity of butadiene and its epoxide metabolites: II. Mutational spectra of butadiene, 1,2-epoxybutene and diepoxybutane at the hprt locus in splenic T cells from exposed B6C3F1 mice [12].
• Molecular analysis of lacI mutants from transgenic fibroblasts exposed to 1,2-epoxybutene [13].

Associations of Epoxybutene with other chemical compounds

• The purpose of the present study was to examine the production and disposition of two mutagenic BD metabolites, butadiene monoepoxide (BDO) and butadiene diepoxide (BDO2), in blood and other tissues of rats and mice during and following inhalation exposures to a target concentration of 62.5 p.p.m. BD [14].
• Comparison of the biotransformation of 1,3-butadiene and its metabolite, butadiene monoepoxide, by hepatic and pulmonary tissues from humans, rats and mice [15].
• Characterization of four N-3-thymidine adducts formed in vitro by the reaction of thymidine and butadiene monoxide [16].
• Influence of GSTM1 genotype on sister chromatid exchange induction by styrene-7,8-oxide and 1,2-epoxy-3-butene in cultured human lymphocytes [17].
• By using these methods, we found alkylation of calf thymus DNA exposed to butadiene monoepoxide in vitro at adenine N6 and guanine N7 sites [18].

Gene context of Epoxybutene

• In vitro sensitivity to the genotoxicity of 1,2:3,4-diepoxybutane, an epoxide metabolite of 1,3-butadiene has clearly been shown to depend on GSTT1 genotype, which has also been implicated to modify, along with GSTM1 genotype, the in vitro genotoxicity of 1,2-epoxy-3-butene, another epoxide metabolite of 1,3-butadiene [19].
• Oxidation of butadiene to 1,2-epoxy-3-butene (BMO) and further activation to BDE is catalysed by cytochrome P450 (CYP) isozymes [10].
• Mutagenicity of the racemic mixtures of butadiene monoepoxide and butadiene diepoxide at the Hprt locus of T-lymphocytes following inhalation exposures of female mice and rats [20].
• The observation that the concentration of butadiene monoepoxide (BMO) is greater in bone marrow than in the blood following inhalation of 1,3-butadiene (BD) by B6C3F1 mice prompted the present investigation into whether cytochrome P450 2E1, the isozyme believed to be involved in the epoxidation of BD, is present in the bone marrow of B6C3F1 mice [21].
• The circular dichroism spectral studies with R and S 3,4-epoxy-1-butene revealed that the reaction mechanism at aqueous neutral pH media is more similar to SN2-type rather than SN1-type [22].

Analytical, diagnostic and therapeutic context of Epoxybutene

• The most sensitive stage to the action of BMO and DEB was preleptotene (meiotic S phase) harvested at 18-day time intervals after treatment [23].
• The methods were applied in vitro [calf thymus DNA and TK6 cell cultures treated with epoxy metabolites of BD, 3,4-epoxy-1-butene (EB) and diepoxybutane (DEB)] and in vivo [DNA isolated from tissues of BD-exposed laboratory animals] [24].
• After treatment with 1,2-epoxybutene in the Comet assay, there was a response in the testes in mice but not in rats and there was little or no effect in the bone marrow assay in mice but there was in rats [25].
• The adducts were prepared by reacting purine nucleobases or nucleosides with epoxybutene (EB) or diepoxybutane (DEB) followed by HPLC separation [26].

References