Metabolism of 1,3-butadiene to butadiene monoxide in mouse and human bone marrow cells

Maniglier-Poulet, Christopher; Cheng, Xiaoqin; Ruth, James A.; Ross, David

doi:10.1016/0009-2797(95)03612-p

Cited by 17 publications

(3 citation statements)

References 28 publications

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“…However, Thornton-Manning recently detected low levels of BDE (≈50-fold less than mice) in rats exposed to BD (62.5 ppm) by inhalation (10). BD can also undergo oxidation to BMO by peroxidases, including human myeloperoxidase (16), and in bone marrow cell lysates in vitro (17). The oxidation of BD can also lead to the production of 3-butenal and crotonaldehyde in vitro (16,(18)(19)(20).…”

Section: Introductionmentioning

confidence: 99%

Characterization of Urinary Metabolites from Sprague-Dawley Rats and B6C3F1 Mice Exposed to [1,2,3,4-¹³C]Butadiene

Nauhaus

Fennell

Asgharian

et al. 1996

Chem. Res. Toxicol.

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1,3-Butadiene (BD) is used in the production of synthetic rubber and other resins. Carcinogenic effects have been observed in laboratory animals exposed to BD, with mice being more sensitive than rats. Metabolic oxidation of butadiene to epoxides is believed to be a crucial step in the initiation of tumors by BD. However, limited information is available that describes the in vivo metabolism of BD. Male Sprague-Dawley rats and B6C3F1 mice were exposed to 800 ppm [1,2 3,4-13C]butadiene for 5 h, and urine was collected during and for 20 h following exposure. Urinary metabolites were characterized using 1- and 2-dimensional methods of NMR spectroscopy. Three metabolites previously detected in vivo, N-acetyl-S-(2-hydroxy-3-butenyl)-L-cysteine, N-acetyl-S-(1-(hydroxymethyl)-2-propenyl)-L-cysteine, and N-acetyl-S-(3,4-dihydroxybutyl)-L-cysteine, were present in both rat and mouse urine, accounting for 87% and 73% of the total metabolites excreted, respectively. A fourth metabolite, previously detected in vitro, 3-butene-1,2-diol, was also present in both rat and mouse urine and comprised 5% and 3% of the total metabolites excreted, respectively. An additional metabolite detected only in mouse urine that is derived from glutathione conjugation with epoxybutene was identified as S-(1-(hydroxymethyl)-2-propenyl)-L-cysteine (4%). N-Acetyl-S-(1-hydroxy-3-butenyl)-L-cysteine (4%), detected in mouse urine, is a thiohemiacetal product of 3-butenal. Additionally, mice excreted N-acetyl-S-(3-hydroxypropyl)-L-cysteine (5%) and N-acetyl-S-(2-carboxyethyl)-L-cysteine (5%), which could be derived from further metabolism of N-acetyl-S-(3,4-dihydroxybutyl)-L-cysteine or from glutathione conjugation with acrolein. Mice excreted N-acetyl-S-(1-(hydroxymethyl)-3,4-dihydroxypropyl)-L-cysteine (5%), which could be derived from glutathione conjugation with diepoxybutane (BDE), while rats excreted 1,3-dihydroxypropanone (5%), which may be derived from hydrolysis of BDE. These studies indicate that reactive aldehydes are produced as metabolites of BD in vivo, in addition to the reactive monoepoxide and diepoxide of BD. The greater toxicity of BD in mice compared with rats may be attributed to the greater ability of rats to detoxify BDE via hydrolysis, and/or to the production of reactive aldehydes.

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Section: Introductionmentioning

confidence: 99%

Characterization of Urinary Metabolites from Sprague-Dawley Rats and B6C3F1 Mice Exposed to [1,2,3,4-¹³C]Butadiene

Nauhaus

Fennell

Asgharian

et al. 1996

Chem. Res. Toxicol.

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“…Butadiene or EB is oxidized principally in the liver via cytochrome P-450 enzymes. Although not extensively investigated, oxidation by other enzymes (possibly myeloperoxidase; Elfarra etal., 1996) may occur to a more limited degree in the bone marrow (e.g., Maniglier-Poulet et al, 1995), based on in vitro observations and the detection of the epoxides in this tissue in rodents (Thornton-Manning et al, 1995a.…”

Section: Toxicokinetics and Metabolismmentioning

confidence: 99%

1,3-Butadiene: Exposure Estimation, Hazard Characterization, and Exposure-Response Analysis

Hughes

Walker

et al. 2003

Journal of Toxicology and Environmental Health, Part B

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1,3-Butadiene has been assessed as a Priority Substance under the Canadian Environmental Protection Act. The general population in Canada is exposed to 1,3-butadiene primarily through ambient air. Inhaled 1,3-butadiene is carcinogenic in both mice and rats, inducing tumors at multiple sites at all concentrations tested in all identified studies. In addition, 1,3-butadiene is genotoxic in both somatic and germ cells of rodents. It also induces adverse effects in the reproductive organs of female mice at relatively low concentrations. The greater sensitivity in mice than in rats to induction of these effects by 1,3-butadiene is likely related to species differences in metabolism to active epoxide metabolites. Exposure to 1,3-butadiene in the occupational environment has been associated with the induction of leukemia; there is also some limited evidence that 1,3-butadiene is genotoxic in exposed workers. Therefore, in view of the weight of evidence of available epidemiological and toxicological data, 1,3-butadiene is considered highly likely to be carcinogenic, and likely to be genotoxic, in humans. Estimates of the potency of butadiene to induce cancer have been derived on the basis of both epidemiological investigation and bioassays in mice and rats. Potencies to induce ovarian effects have been estimated on the basis of studies in mice. Uncertainties have been delineated, and, while there are clear species differences in metabolism, estimates of potency to induce effects are considered justifiably conservative in view of the likely variability in metabolism across the population related to genetic polymorphism for enzymes for the critical metabolic pathway.

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“…BD has marked species differences in susceptibility to the carcinogenic effect, possibly due to differences in metabolism [37][38][39][40]. BD is metabolized by the cytochrome P-450-dependent monoxygenases to 1,2-epoxybutene-3 (EB), which is further metabolized by oxidation to diepoxybutane (DEB) [39][40][41]. DEB is a bifunctional alkylating agent that induces interstrand and intrastrand DNA-DNA crosslinks by alkylating two adjacent bases within the major grove of a DNA duplex [42,43] and DNA-protein crosslinks [44][45][46].…”

Section: Introductionmentioning

confidence: 99%

DNA Repair Decline During Mouse Spermiogenesis Results in the Accumulation of Heritable DNA Damage

Marchetti¹,

Wyrobek²

2007

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The post-meiotic phase of mouse spermatogenesis (spermiogenesis) is very sensitive to the genomic effects of environmental mutagens because as male germ cells form mature sperm they progressively lose the ability to repair DNA damage. We hypothesized that repeated exposures to mutagens during this repair-deficient phase result in the accumulation of heritable genomic damage in mouse sperm that leads to chromosomal aberrations in zygotes after fertilization. We used a combination of single or fractionated exposures to diepoxybutane (DEB), a component of tobacco smoke, to investigate how differential DNA repair efficiencies during the three weeks of spermiogenesis affected the accumulation of DEB-induced heritable damage in early spermatids (21-15 days before fertilization, dbf), late spermatids (14-8 dbf) and sperm (7-1 dbf). Analysis of chromosomal aberrations in zygotic metaphases using PAINT/DAPI showed that late spermatids and sperm are unable to repair DEB-induced DNA damage as demonstrated by significant increases (P<0.001) in the frequencies of zygotes with chromosomal aberrations. Comparisons between single and fractionated exposures suggested that the DNA repair-deficient window during late spermiogenesis may be less than two weeks in the mouse and that during this repair-deficient window there is accumulation of DNA damage in sperm.Finally, the dose-response study in sperm indicated a linear response for both single and repeated exposures. These findings show that the differential DNA repair capacity of post-meioitic male germ cells has a major impact on the risk of paternally transmitted heritable damage and suggest that chronic exposures that may occur in the weeks prior to fertilization because of occupational or lifestyle factors (i.e, smoking) can lead to an accumulation of genetic damage in sperm and result in heritable chromosomal aberrations of paternal origin.

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Metabolism of 1,3-butadiene to butadiene monoxide in mouse and human bone marrow cells

Cited by 17 publications

References 28 publications

Characterization of Urinary Metabolites from Sprague-Dawley Rats and B6C3F1 Mice Exposed to [1,2,3,4-¹³C]Butadiene

Characterization of Urinary Metabolites from Sprague-Dawley Rats and B6C3F1 Mice Exposed to [1,2,3,4-¹³C]Butadiene

1,3-Butadiene: Exposure Estimation, Hazard Characterization, and Exposure-Response Analysis

DNA Repair Decline During Mouse Spermiogenesis Results in the Accumulation of Heritable DNA Damage

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Metabolism of 1,3-butadiene to butadiene monoxide in mouse and human bone marrow cells

Cited by 17 publications

References 28 publications

Characterization of Urinary Metabolites from Sprague-Dawley Rats and B6C3F1 Mice Exposed to [1,2,3,4-13C]Butadiene

Characterization of Urinary Metabolites from Sprague-Dawley Rats and B6C3F1 Mice Exposed to [1,2,3,4-13C]Butadiene

1,3-Butadiene: Exposure Estimation, Hazard Characterization, and Exposure-Response Analysis

DNA Repair Decline During Mouse Spermiogenesis Results in the Accumulation of Heritable DNA Damage

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Product

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Characterization of Urinary Metabolites from Sprague-Dawley Rats and B6C3F1 Mice Exposed to [1,2,3,4-¹³C]Butadiene

Characterization of Urinary Metabolites from Sprague-Dawley Rats and B6C3F1 Mice Exposed to [1,2,3,4-¹³C]Butadiene