Identification and quantitation of 1,2-epoxybutene-3 as the primary metabolite of 1,3-butadiene

Malvoisin, Etienne; Lhoëst, Georges; Poncelet, F.; Roberfroid, Marcel; Mercier, Michel

doi:10.1016/s0021-9673(00)92500-7

Cited by 86 publications

(25 citation statements)

References 6 publications

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“…Previous studies on the pathogenesis of the BD-induced lesions reveal that they are preceded by functional alterations in early HPC populations and activation of endogenous ecotropic retrovirus (28)(29)(30). The toxicity of BD is dependent on metabolism, with the predominant metabolite being the 3,4-epoxybutene (EB) (31)(32)(33)(34). To clarify the role of altered hematopoietic stem and progenitor cell regulation in the pathogenesis of hematopoietic injury associated with BD, we examined the influence of in vitro pretreatment with EB on cytokine growth response in murine bone marrow cells.…”

mentioning

confidence: 99%

Chemical suppression of a subpopulation of primitive hematopoietic progenitor cells: 1,3-butadiene produces a hematopoietic defect similar to steel or white spotted mutations in mice.

Colagiovanni¹,

Stillman²,

Irons³

1993

Proc. Natl. Acad. Sci. U.S.A.

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Chronic exposure of mice to 1,3-butadiene produces a macrocytic-megaloblastic anemia, thymic hypoplasia, and an increased incidence of T-ceU lymphoma/leukemia. This is reminiscent of pathologies observed in mice bearing mutations at the W and SI loci, which are deficient in c-kit and c-kit ligand (CKL), respectively. 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, SI, and W mice was investigated in order to elucidate the role of altered HPC regulation in the pathogenesis of 1,3-butadiene toxicity. EB pretreatment suppressed interleukin 3 colony formation and abrogated CKL

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mentioning

confidence: 99%

Chemical suppression of a subpopulation of primitive hematopoietic progenitor cells: 1,3-butadiene produces a hematopoietic defect similar to steel or white spotted mutations in mice.

Colagiovanni¹,

Stillman²,

Irons³

1993

Proc. Natl. Acad. Sci. U.S.A.

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“…Furthermore, a simple gas chromatographic method f~ the quantitative determination of MEP has been developed This headspace method allows the determination of the total amount of MEP, whereas other assays involvin~ volatile epoxides are mostly limited to the quantitation 0f the epoxide formation in the liquid (Malvoisin et al 1979) or in the gas phase (Schmidt et el. 1985).…”

Section: Discussionmentioning

confidence: 99%

“…It has already been demonstrated that several important industrial chemicals such as 1,3-butadiene, cyclohexadiene, styrene and isoprene are metabolized to epoxides (Salmona et al 1976;Watabe et al 1978;Malvoisin et al 1979;Gervasi et al 1982;Malvoisin and Roberfroid 1982;Bolt et al 1983;Del Monte et al 1985). Certain of these seemed to be mutagenic, but it is clear that the adverse properties of 264 some arene and alkene oxides can not be simply extrapolated to epoxides in general (Oesch 1976).…”

Section: Introductionmentioning

confidence: 99%

In vitro biotransformation of 2-methylpropene (isobutene): Epoxide formation in mice liver

et al. 1991

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Until now, no data are available concerning the biotransformation and toxicity of 2-methylpropene (or isobutene), a gaseous alkene widely used in industry (rubber, fuel additives, plastic polymers, adhesives, antioxidants). In this work, the biotransformation of 2-methylpropene (MP) has been studied, using total liver homogenates of mice, supplemented with a NADPH-generating system. In analogy to other olefins, 2-methylpropene is metabolized to its epoxide 2-methyl-1,2-epoxypropane (MEP), as proved by the identification by gas chromatography coupled with mass spectrometry. The epoxidation is cytochrome P-450 dependent, as shown by experiments in the absence of the NADPH-generating system and in the presence of various concentrations of metyrapone and SKF 525-A, two known inhibitors of the mono-oxygenases. A simple gas chromatographic headspace method has been developed for the quantitative determination of the epoxide formed. The formation of MEP is never linear in function of time and it reaches a maximum after 20 min. Thereafter is decreases continuously to undetectable levels. This observation can be explained by the immediate action of epoxide hydrolase and glutathione S-transferase, converting the epoxide to 2-methyl-1,2-propanediol and to the glutathione conjugate respectively. The involvement of both enzymes has been demonstrated by the addition of 3,3,3-trichloropropene oxide and indomethacin. These inhibitors of, respectively, epoxide hydrolase and glutathione S-transferase increase the epoxide formation in a significant way. The actual concentration of MEP is therefore not only dependent on its formation by cytochrome P-450 dependent mono-oxygenases, but also on its conversion by epoxide hydrolase and glutathione S-transferase, both very active in liver tissue.

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“…Both compounds induce increases in the frequency of sister chromatid exchanges in bone marrow cells and in the levels of micronucleated erythrocytes in peripheral blood of mice (7,18); both compounds can be metabolized to monoepoxide and diepoxide intermediates by liver microsomal monooxygenases (8,9,19,20), the diepoxide intermediates of both compounds are mutagenic in Salmonella (10,21); both compounds cause reductions in red blood cell counts, hemoglobin concentrations, and volume of packed red cells in mice; and both compounds produced olfactory epithelial changes, testicular atrophy, and forestomach epithelial hyperplasia in mice. Due to these similarities, 13- exposure studies of isoprene at concentrations ranging from 70 to 7000 ppm have been initiated in F344 rats and B6C3F1 mice to determine whether isoprene acts similar to 1,3-butadiene after longer exposure durations.…”

Section: Discussionmentioning

confidence: 99%

Inhalation Toxicology of Isoprene in F344 Rats and B6C3F 1 Mice Following Two-Week Exposures

Melnick¹,

Roycroft²,

Chou³

et al. 1990

Environmental Health Perspectives

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Isoprene (2-methyl-1,3-butadiene) was selected for toxicologic evaluations because of its structural similarity to 1,3-butadiene, a potent rodent carcinogen. Two-week inhalation toxicology studies of isoprene were conducted in F344 rats and B6C3F1 mice at exposure concentrations of 0, 438, 875, 1750, 3500, or 7000 ppm. For rats, there were no chemically related changes in survival, body weight gain, clinical signs, hematologic or clinical chemistry parameters, or gross or microscopic lesions. Exposure of mice to isoprene did not produce mortalities and only caused a decrease in body weight gain for male mice in the 7000 ppm exposure group; however, hematologic changes and microscopic lesions including testicular atrophy, olfactory epithelial degeneration, and forestomach epithelial hyperplasia were observed in isoprene-exposed mice. Similar toxicologic effects have been previously observed in B6C3F1 mice exposed to 1,3-butadiene. A species difference in susceptibility between rats and mice exposed to isoprene was evident in these short-term exposure studies.

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Identification and quantitation of 1,2-epoxybutene-3 as the primary metabolite of 1,3-butadiene

Cited by 86 publications

References 6 publications

Chemical suppression of a subpopulation of primitive hematopoietic progenitor cells: 1,3-butadiene produces a hematopoietic defect similar to steel or white spotted mutations in mice.

Chemical suppression of a subpopulation of primitive hematopoietic progenitor cells: 1,3-butadiene produces a hematopoietic defect similar to steel or white spotted mutations in mice.

In vitro biotransformation of 2-methylpropene (isobutene): Epoxide formation in mice liver

Inhalation Toxicology of Isoprene in F344 Rats and B6C3F 1 Mice Following Two-Week Exposures

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