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PubMedDate not supplied

Species and tissue differences in the microsomal oxidation of 1,3-butadiene and the glutathione conjugation of butadiene monoxide in mice and rats. Possible role in 1,3-butadiene-induced toxicity.

Rat and mouse liver, lung, and kidney microsomes metabolized 1,3-butadiene to butadiene monoxide (BM), whereas microsomes from testis, one of the target organs of 1,3-butadiene toxicity in both species, were ineffective. 1,3-Butadiene metabolism was NADPH-dependent and inhibited by 1-benzylimidazole. With mouse microsomes, a 4-fold higher rate was measured with kidney compared with liver or lung, which exhibited similar rates. With rat microsomes, the rate obtained with liver was 2- and 6-fold higher than those of lung and kidney, respectively. Overall, oxidation rates by mouse tissues were higher than those of rat tissues. These results, along with the finding that BM was stable in the presence of rat plasma, provide evidence for the role of circulating metabolites in 1,3-butadiene-induced toxicity. Furthermore, crotonaldehyde, a known carcinogen, was detected with mouse tissues only. Thus, in addition to the greater ability of mouse tissues to produce BM, formation of crotonaldehye may contribute to the greater susceptibility of mice to 1,3-butadiene toxicity compared with rats. Nearly all rat liver glutathione S-transferase activity was localized to the cytosol (greater than 96%). BM glutathione conjugation rates with liver cytosol of both species were similar, whereas conjugation rates with mouse lung and kidney cytosol were 4- and 2-fold higher than those of rat lung and kidney, respectively. Thus, species differences in BM glutathione conjugation do not correlate with species susceptibility.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1995

Disposition of butadiene monoepoxide and butadiene diepoxide in various tissues of rats and mice following a low-level inhalation exposure to 1,3-butadiene.

1,3-Butadiene (BD), a chemical used extensively in the production of styrene-butadiene rubber, is carcinogenic in Sprague-Dawley rats and B6C3F1 mice. Chronic inhalation studies revealed profound species differences in the potency and organ-site specificity of BD carcinogenesis between rats and mice. BD is a potent carcinogen in mice and a weak carcinogen in rats. Previous studies from our laboratory and others have shown marked differences between rats and mice in the metabolism of BD, which may account for species differences in carcinogenicity. 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. BDO was increased above background in blood, bone marrow, heart, lung, fat, spleen and thymus tissues of mice after 2 h and 4 h exposures to BD. In rats, levels of BDO were increased in blood, fat, spleen and thymus tissues. No increases in BDO were observed in rat lungs. BDO2, the more mutagenic of the two epoxides, was increased in the blood of rats and mice at 2 and 4 h after initiation of exposure to BD. In mice, BDO2 was detected in all tissues examined immediately following the 4 h exposure. This metabolite was detected in heart, lung, fat, spleen and thymus of rats, but at levels 40- to 160-fold lower than those seen in mice. Immediately after the 4 h exposure, blood levels of BDO2 were 204 +/- 15 pmol/g for mice but were 41-fold lower for rats. In the sensitive mouse target organs, heart and lungs, levels of BDO2 exceeded BDO levels immediately after the exposure. This study shows that the levels of BD epoxides are markedly greater in the mouse BD target organs. The high concentrations of BDO2 in these organs suggest that this compound may be particularly important in BD-induced carcinogenesis. Thus, although BD is oxidatively metabolized by similar metabolic pathways in rats and mice, the substantial quantitative differences in tissue levels of mutagenic epoxides between species may be responsible for the increased sensitivity of mice to BD-induced carcinogenicity.

Administration, Inhalation↗

PubMed1996

Gender and species differences in the metabolism of 1,3-butadiene to butadiene monoepoxide and butadiene diepoxide in rodents following low-level inhalation exposures.

Levels of butadiene monoepoxide (BDO) and butadiene diepoxide (BDO2) were compared in tissues of male Sprague-Dawley rats and male B6C3F1 mice and in tissues of male and female Sprague-Dawley rats following inhalation exposures to 62.5 ppm 1,3-butadiene (BD). In male rats, BDO2 levels were highest in blood and were present at a concentration of only 5 +/- 1 pmol/g. Following a 6-h exposure, the concentration of BDO2 in the blood, femurs, lung and fat of female rats was 3 to 7-fold that of male rats. Levels of BDO were similar in tissues of female and male rats. Generally, levels of BDO were approximately 3 to 8-fold greater in mouse tissues as compared with rat tissues following 4-h exposures to BD. In blood, 204 +/- 15 pmol/g BDO2 was detected in male mice, while in rats, blood BDO2 levels were 5 +/- 1 pmol/g. This study shows marked species differences in tissue levels of BD epoxides, particularly BDO2, in rats and mice, and is the first to show gender differences in BD metabolism.

Administration, Inhalation↗

PubMed1995

Analysis of butadiene, butadiene monoxide, and butadiene dioxide in blood by gas chromatography/gas chromatography/mass spectroscopy.

A new method was developed to quantify the levels of 1,3-butadiene (BD), butadiene monoxide (BDO), and butadiene diepoxide (BDO2) in blood. The method was based on vacuum distillation of tissues followed by analysis of the distillates using multidimensional GC/MS. Metabolites isolated from blood by vacuum distillation were condensed into a cold trap. After warming the traps to room temperature, BD and BDO were sampled from the trap vapor phase. BDO2 was extracted from the codistilled water phase using ethyl acetate. Samples were analyzed using a multidimensional GC system equipped with a custom-built interface. The method was validated by analysis of 0.75-mL aliquots of mouse blood spiked with 5.0, 3.4, and 0.55 nmol of BD, BDO, and BDO2, respectively. The recoveries of analytes were 96 +/- 18%, 125 +/- 15%, and 98 +/- 12%, respectively (mean +/- SD, n = 6). Kinetic studies indicated no loss of BDO and BDO2 in blood held at room temperature in closed containers for up to 1 h. The method was applied to blood samples from B6C3F1 mice and Sprague-Dawley rats exposed by inhalation (nose-only) to 100 ppm BD for 4 h. Blood levels of BD and BDO in exposed rats were 4.1 +/- 1.0 and 0.10 +/- 0.06 microM, respectively (mean +/- SD, n = 6). Levels of BDO2 were below the limits of detection (0.01 nmol/mL). Blood levels of BD, BDO, and BDO2 in mice exposed to 100 ppm BD for 4 h were 2.9 +/- 1.3, 0.38 +/- 0.14, and 0.33 +/- 0.19 microM, respectively (mean +/- SD, n = 6).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Comparison of blood concentrations of 1,3-butadiene and butadiene epoxides in mice and rats exposed to 1,3-butadiene by inhalation.

1,3-Butadiene (BD), an important commodity chemical used in the production of synthetic rubber, is carcinogenic in B6C3F1 mice and Sprague-Dawley rats, raising concern for potential carcinogenicity in humans. Mice are more sensitive than rats to the carcinogenic effects of BD. Metabolic activation of BD to form the putative DNA-reactive metabolites, butadiene monoxide (BMO) and butadiene diepoxide (BDE), is mediated by cytochrome P450. Detoxication of the epoxides occurs by glutathione S-transferase-catalyzed conjugation with glutathione and hydrolysis by epoxide hydrolase. Species differences in metabolic activation and detoxication most likely contribute to the difference in carcinogenic potency of BD by modulating the circulating blood levels of the epoxides. This study measured the in vivo concentrations of BD, BMO and BDE in the blood of male Sprague-Dawley rats and B6C3F1 mice during and following 6 h nose-only exposure to inhaled BD at 62.5, 625 or 1250 p.p.m. BD. Blood samples for BD and BMO (> or = 3 samples/time point) were collected at 2, 3, 4 and 6 h of exposure. Blood samples for BDE were collected at 3 and 6 h of exposure. After exposure, blood samples for BD, BMO and BDE were collected at 2-10 min intervals up to 30 min post-exposure. BD was quantified by gas chromatography using a vial headspace equilibration technique. BD epoxides were extracted into methylene chloride and quantified by gas chromatography-mass spectrometry. The concentration of BD in blood was not directly proportional to the inhaled concentration of BD, suggesting that the uptake of BD was saturable at the highest inhaled concentration. In both rats and mice, BD and BMO blood levels were at steady-state at 2, 3, 4 and 6 h of exposure, and declined rapidly after removal from exposure to BD. Steady-state blood concentrations of BD were 2.4, 37 and 58 microM in mice and 1.3, 18 and 37 microM in rats exposed to 62.5, 625 and 1250 p.p.m. BD respectively. Both species formed BMO from BD. In mice the respective steady-state BMO concentrations in blood were 0.6, 3.7 and 8.6 microM, compared to BMO blood concentrations in rats of 0.07, 0.94 and 1.3 microM. Mice, but not rats, had quantifiable levels of BDE in the blood. The peak concentrations of BDE in the blood of mice at 6 h were 0.65, 1.9 and 2.5 microM.(ABSTRACT TRUNCATED AT 400 WORDS)

Administration, Inhalation↗

PubMed1997

In vitro and in vivo mutagenicity of the butadiene metabolites butadiene diolepoxide, butadiene monoepoxide and diepoxybutane.

Three metabolites of 1,3-butadiene, namely butadiene diolepoxide, butadiene monoepoxide and diepoxybutane, were tested in the bacterial mutation assay using Salmonella typhimurium strain TA100 with and without metabolic activation (S9 mix). All three compounds showed a mutagenic response. The bifunctional epoxide was more effective than the diolepoxide which was more effective than the monoepoxide. Toxicity appeared to follow the ranking of the chemicals for their mutagenic potency. The monoepoxide and the diolepoxide were also tested for induction of micronuclei in mouse bone marrow erythrocytes and for dominant lethal mutation induction in postmeiotic male mouse germ cells. The effects of the diepoxide in both in vivo tests have been published earlier. In the micronucleus assay, the three metabolites gave a positive response whereby the diepoxide was more effective than the monoepoxide which was more effective than the diolepoxide. In contrast to the diepoxide which was positive at a dose as low as 36 mg/kg, the monoepoxide and the diol did not show an induction of dominant lethal effects up to doses of 120 and 240 mg/kg, respectively. It is concluded that the metabolites were mutagenic in bacteria without metabolic activation and clastogenic in mouse bone marrow; only the bifunctional diepoxide, however, was active in postmeiotic male mouse germ cells.

Animals↗

PubMed1988

Metabolism of 1,3-butadiene by lung and liver microsomes of rats and mice repeatedly exposed by inhalation to 1,3-butadiene.

1,3-Butadiene, a colorless gas widely used as an intermediate in the production of synthetic rubber, is carcinogenic in rats and mice. Species differences exist in the sensitivity to inhaled 1,3-butadiene and the target tissue specificity for tumor formation. We examined whether repeated inhalation exposure of rats and mice to 1,3-butadiene would affect the rate of metabolism of 1,3-butadiene by lung and liver microsomes in these species. Male Sprague-Dawley rats and B6C3F1 mice were exposed nose-only to air (control) or 7600 +/- 170 ppm 1,3-butadiene (13,600 +/- 300 micrograms/l) and 740 +/- 10 ppm 1,3-butadiene (1300 +/- 20 micrograms/l), respectively, for 6 h/day for 5 days. After the last exposure, nasal tissue (rats only), lungs and livers were removed from the animals and microsomes were prepared. Microsomes from the different tissues were incubated with 6 mumol 1,3-butadiene and 10 mumol NADPH for 30 min and the rate of disappearance of 1,3-butadiene from the reaction flasks was quantitated. There was a statistically significant (P less than 0.05) depression in the rate of 1,3-butadiene metabolism (50%) in microsomes from lungs of both rats and mice that were exposed repeatedly to 1,3-butadiene compared to control animals. There was no effect of repeated 1,3-butadiene exposure on liver or nasal tissue (rats only) metabolism of 1,3-butadiene in rats or mice. The data from these studies indicate that it is unlikely that species differences in sensitivity or tissue susceptibility are due to an inductive or inhibitory effect of 1,3-butadiene on its own metabolism in the tissues examined.

Administration, Inhalation↗

PubMed1991

Mechanisms of 1,3-butadiene oxidations to butadiene monoxide and crotonaldehyde by mouse liver microsomes and chloroperoxidase.

NADPH-dependent oxidation of 1,3-butadiene by mouse liver microsomes or H2O2-dependent oxidation by chloroperoxidase produced both butadiene monoxide and crotonaldehyde; methyl vinyl ketone and 2,3- and 2,5- dihydrofuran were not detected. The crotonaldehyde to butadiene monoxide ratio remained constant over time in both the microsomal and the chloroperoxidase reactions; however, much more crotonaldehyde was produced by chloroperoxidase than microsomes; crotonaldehyde was not detected when reference samples of butadiene monoxide were used in control incubations containing NADPH and microsomes or H2O2 and chloroperoxidase. Moreover, incubations of 1,3-butadiene with horseradish peroxidase and H2O2, or microsomes and H2O2 or arachidonic acid did not result in the oxidation of 1,3-butadiene. In microsomes, metabolite formation was dependent on incubation time, NADPH, and protein concentrations and did not change when the 1,3-butadiene pressure was varied between 24 and 52 cm Hg. Inclusion of the cytochrome P450 inhibitor 1-benzylimidazole inhibited 1,3-butadiene metabolism, but inclusion of KCN, catalase, or superoxide dismutase had no effect. These results support the role of cytochrome P450 in 1,3-butadiene oxidation by mouse liver microsomes. The formation of crotonaldehyde but not methyl vinyl ketone by cytochrome P450 or chloroperoxidase indicates regioselectivity in the oxygen transfer from the hemoproteins to 1,3-butadiene. The intermediates formed may undergo either ring closure to form butadiene monoxide or a hydrogen shift to form 3-butenal which tautomerizes to produce crotonaldehyde. Evidence for this tautomerization was obtained by the finding that 3-buten-1-ol, an alternative precursor of 3-butenal, was oxidized to crotonaldehyde under incubation conditions similar to that used for 1,3-butadiene.

Aldehydes↗

PubMed1997

Haemoglobin adducts of epoxybutanediol from exposure to 1,3-butadiene or butadiene epoxides.

Epoxybutanediol is one of the reactive metabolites of butadiene. It is formed via hydrolysis followed by oxidation of the primary metabolite of butadiene, epoxybutene, or via hydrolysis of diepoxybutane, a secondary metabolite of butadiene. Groups of male Sprague Dawley rats were treated by intraperitoneal injection of epoxybutene, epoxybutanediol or diepoxybutane. N-(2,3,4-Trihydroxybutyl)valine adducts in haemoglobin, formed from epoxybutanediol in its reaction with N-terminal valine, were measured using the N-alkyl Edman method followed by acetylation of the Edman derivatives and analysis by gas chromatography mass spectrometry. The same adducts were also measured in male Wistar rats exposed to butadiene by inhalation and in a few workers with occupational exposure to butadiene. Haemoglobin binding indexes, HBI, (pmol adduct/g per mumol of alkylating agent, or, for butadiene, per ppm x h), were calculated. The HBI for epoxybutanediol (about 10) is comparable to that of ethylene oxide in the rat demonstrating a similar capacity of the two compounds to alkylate nucleophilic sites in vivo. The HBI of diepoxybutane (about 8) for epoxybutanediol adduct formation is approximately the same as that of epoxybutanediol itself. Epoxybutanediol adduct formation was nonlinearly related to exposure in butadiene exposed rats. The epoxybutanediol-haemoglobin adduct levels were substantially higher than those of epoxybutene in both butadiene-exposed rats and humans suggesting an important role of epoxybutanediol in the toxicity of butadiene. Adducts of epoxybutanediol are probably useful for biomonitoring of human exposure to butadiene.

Air Pollutants, Occupational↗

PubMed1999

Multiple organ carcinogenicity of inhaled chloroprene (2-chloro-1,3-butadiene) in F344/N rats and B6C3F1 mice and comparison of dose-response with 1,3-butadiene in mice.

Chloroprene (2-chloro-1,3-butadiene) is a high production chemical used almost exclusively in the production of polychloroprene (neoprene) elastomer. Because of its structural similarity to 1,3-butadiene, a trans-species carcinogen, inhalation studies were performed with chloroprene to evaluate its carcinogenic potential in rats and mice. Groups of 50 male and female F344/N rats and 50 male and female B6C3F1 mice were exposed to 0, 12.8, 32 or 80 p.p.m. chloroprene (6 h/day, 5 days/week) for 2 years. Under these conditions, chloroprene was carcinogenic to the oral cavity, thyroid gland, lung, kidney and mammary gland of rats, and to the lung, circulatory system (hemangiomas and hemangiosarcomas), Harderian gland, kidney, forestomach, liver, mammary gland, skin, mesentery and Zymbal's gland of mice. Survival adjusted tumor rates in mice were fit to a Weibull model for estimation of the shape of the dose-response curves, estimation of ED10 values (the estimated exposure concentration associated with an increased cancer risk of 10%) and comparison of these parameters with those for 1,3-butadiene. Butadiene has been identified as a potent carcinogen in mice and has been associated with increased risk of lymphatic and hematopoietic cancer in exposed workers. Shape parameter values for most of the neoplastic effects of chloroprene and 1,3-butadiene were consistent with linear or supralinear responses in the area near the lowest tested exposures. The most potent carcinogenic effect of 1,3-butadiene was the induction of lung neoplasms in female mice, which had an ED10 value of 0.3 p.p.m. Since the ED10 value for that same response in chloroprene exposed mice was also 0.3 p.p.m., we conclude that the carcinogenic potency of chloroprene in mice is similar to that of 1,3-butadiene. Cancer potency of chloroprene is greater in the mouse lung than in the rat lung, but greater in the rat kidney than in the mouse kidney and nearly equivalent in the mammary gland of each species.

Administration, Inhalation↗

PubMed1998

Disposition of butadiene epoxides in Sprague-Dawley rats following exposures to 8000 ppm 1,3-butadiene: comparisons with tissue epoxide concentrations following low-level exposures.

1,3-Butadiene (BD), a compound used extensively in the rubber industry, is weakly carcinogenic in Sprague-Dawley rats after chronic exposures to concentrations of 1000 and 8000 ppm. Conversely, in B6C3F1 mice, tumors occur after chronic exposures to concentrations as low as 6.25 ppm. Previously, we have shown that tissue concentrations of the mutagenic BD metabolites, butadiene monoepoxide (BDO) and butadiene diepoxide (BDO2), are present in greater concentrations in mice than in rats following acute exposures to low levels (100 ppm or less). This disparity was particularly significant for the diepoxide. We hypothesized that if these epoxides are involved in the carcinogenic response of BD, then they will also be present in rat tissues at relatively high concentrations following exposures to 8000 ppm BD. In the present study, concentrations of the BD epoxides, BDO and BDO2, were determined in blood of female Sprague-Dawley rats following a single 6-h exposure and 10 repeated exposures to a target concentration of 8000 ppm BD. Concentrations of these epoxides were also determined in a number of other tissues, including the primary rat target organ-mammary gland-following 10 repeated exposures. Blood concentrations of BDO were 4030 pmol/g +/- 191 following a 6-h exposure and were 18% lower following the 10-day exposure. Blood concentrations of BDO2, following the 8000 ppm exposures, were very similar to those previously observed after exposures to 62.5 ppm BD (11 +/- 1 and 17 +/- 1 pmol/g following exposures of 6h and 6h/day for 10 days, respectively.) Concentrations of BDO ranged from 740 +/- 110 (femur) to 8990 +/- 1150 (fat) pmol/g tissue. Concentrations of BDO2 were similar among eight tissues analyzed, ranging from 5 +/- 1 (femur) to 17 +/- 3 (heart) pmol/g tissue. Tissue concentrations of butadiene monoepoxide were increased by 17- to 50-fold in tissues from rats exposed by inhalation to 8000 ppm BD as compared to tissues from rats exposed to 62.5 ppm BD. Based on earlier studies at our institute the internal dose of BD increases approximately 14-fold in the 8000 ppm-exposed rats compared to rats exposed to 62.5 ppm BD. Concentrations of butadiene diepoxide in rat tissues following an exposure to 8000 ppm BD were similar to those observed in rat tissues following exposures to 62.5 ppm BD. This study shows that pathways responsible for the accumulation of BDO2 in rats are saturated following low-level BD exposures. This suggests that the primary determinant of BD tumorigenicity in rats is not butadiene diepoxide. The high levels of BDO observed in rat mammary tissue suggest that this metabolite may be a more important determinant of BD carcinogenesis in the rat.

Animals↗

PubMed1985

Species differences in the formation of butadiene monoxide from 1,3-butadiene.

When 1,3-butadiene is incubated with liver postmitochondrial fractions from mouse, rat, monkey or man and a NADPH-regenerating system, the formation rate of butadiene monoxide is different in the four species. With the exception of the rhesus monkey, the amount of epoxide is proportional to the monooxygenase activity. The sequence of epoxide formation is B6C3F1 mouse, Sprague Dawley rat, man, rhesus monkey. The ratio between mouse and monkey was about 7:1. When 1,3-butadiene is incubated with homogenates from lung tissue, only tissues from mouse and rat produce measurable butadiene monoxide concentrations. The monooxygenase activity in lung tissue of the mouse was only 1/30 that in mouse liver. By contrast, lung tissue formed epoxide concentrations comparable to those formed by liver tissue, whereas monkey and human lung tissue did not produce any measurable levels of butadiene monoxide. The data might suggest that the results of recent rodent inhalation studies with 1,3-butadiene could not automatically be extrapolated to man.

7-Alkoxycoumarin O-Dealkylase↗

PubMed1996

Biochemistry of 1,3-butadiene metabolism and its relevance to 1,3-butadiene-induced carcinogenicity.

Recently, the roles of specific P450 isoforms, myeloperoxidase (MPO), GSH-S-transferase and epoxide hydrolase in the metabolism of 1,3-butadiene, and its major oxidative metabolite, butadiene monoxide (BM), were investigated. The results provided evidence for P450s 2A6 and 2E1 being major catalysts of 1,3-butadiene oxidation in human liver microsomes. cDNA-expressed human P450s 2E1, 2A6, and 2C9 catalyzed BM oxidation to meso- and (+/-)-diepoxybutane (DEB), but the rates of BM oxidation in mouse, rat, or human liver microsomes were much lower than the rates of 1,3-butadiene oxidation in these tissues. Human MPO catalyzed 1,3-butadiene oxidation to BM, but MPO incubations with BM did not yield DEB. Rates of BM formation in mouse and human liver microsomes were similar and were nearly 3.4-fold higher than that obtained with rat liver microsomes. However, rat liver epoxide hydrolase activity was nearly 2-fold higher than that of mouse liver microsomes. Rat and mouse liver GSH-S-transferases exhibited similar BM conjugation kinetics, but rats excreted more BM-mercapturic acids compared to mice given low equimolar doses of BM. BM reacted with guanosine and adenosine to yield N7-, N2-, and N1-guanosinyl and N6-adenosinyl adducts, respectively. These results may contribute to a better understanding of the biochemical basis of 1,3-butadiene-induced carcinogenicity.

Animals↗

PubMedDate not supplied

A simplified methodology for quantitation of butadiene metabolites. Application to the study of 1,3-butadiene metabolism by rat liver microsomes.

A rapid, simple extraction and GC assay procedure is described that allows quantitation of micromolar concentrations of butadiene bisoxide and 3-butene-1,2-diol in microsomal suspensions exposed to butadiene. Butane-1,4-diol is used as the internal standard. The recovery of these compounds from aqueous media was almost quantitative, and calibrations for each compound were linear from 10(-6) to 10(-3) M. In this system butadiene monoxide and crotonaldehyde can be rapidly quantitated at micromolar concentration by headspace sampling, using methanol or n-butanol as the internal standard. In addition, the synthesis and chemical characterization of diastereomeric 3,4-epoxybutane-1,2-diols are described. It is demonstrated that the epoxy diol, although not extractable from aqueous solutions by ethyl acetate, can be recovered upon evaporation of aqueous media, followed by ethyl acetate extraction. Direct GC quantitation of the epoxy diol was linear from 10(-5) to 10(-3) M. This procedure facilitated the examination of butadiene metabolism by rat liver microsomes. Exposure of microsomes to butadiene resulted in the NADPH-dependent formation of butadiene monoxide, crotonaldehyde, 3-butene-1,2-diol, and one diastereomer of 3,4-epoxybutane-1,2-diol.

Aldehydes↗

PubMed1984

Inhalation pharmacokinetics based on gas uptake studies. VI. Comparative evaluation of ethylene oxide and butadiene monoxide as exhaled reactive metabolites of ethylene and 1,3-butadiene in rats.

When ethylene oxide or butadiene monoxide is added to the atmosphere of a closed inhalation chamber occupied by Sprague-Dawley rats, a first-order elimination pattern is observed. When either of these compounds is IP injected into rats which are subsequently placed in the closed chamber, the course of epoxide in the atmosphere follows Bateman exponential functions. From the experimental data, the kinetic parameters for distribution and metabolic elimination of ethylene oxide and butadiene monoxide can be derived. When ethylene or 1,3-butadiene was added to the closed exposure systems and kept at atmospheric concentrations which assured maximal metabolic turnover of the olefin (i.e., concentrations above 1,000 ppm ethylene or 1,500 ppm 1,3-butadiene), exhalation of the appropriate epoxide occurred and led finally to a constant (plateau) concentration of the reactive metabolite in the system's atmosphere. Although the initial time-course was different between butadiene monoxide and ethylene oxide (with a high initial increase of ethylene oxide and a subsequent decrease) an analysis at steady-state (plateau concentrations) revealed that only 29% of the amounts of both epoxides which in theory are formed as primary metabolites from the parent olefins are systematically available (i.e., distributed in the entire organism). The discrepancy is probably related to first pass elimination of the epoxide.

Animals↗

PubMed1999

Butadiene diolepoxide- and diepoxybutane-derived DNA adducts at N7-guanine: a high occurrence of diolepoxide-derived adducts in mouse lung after 1,3-butadiene exposure.

Butadiene (BD) is a high production volume chemical and is known to be tumorigenic in rodents. BD is metabolized to butadiene monoepoxide (BMO), diepoxybutane (DEB) and butadiene diolepoxide (BDE). These epoxides are genotoxic and alkylate DNA both in vitro and in vivo, mainly at the N7 position of guanine. In this study, a 32P-post-labeling/thin-layer chromatography (TLC)/high-pressure liquid chromatography (HPLC) assay for BDE and DEB adducts at the N7 of guanine was developed and was used in determining the enantiomeric composition of the adducts and the organ dose of BD exposure in lung. Exposure of 2'-deoxyguanosine (dGuo), 2'-deoxyguanosine-5'-phosphate (5'-dGMP) and 2'-deoxyguanosine-3'-phosphate (3'-dGMP) to racemic BDE followed by neutral thermal hydrolysis gave two products (products 1 and 2) that were identified by MS and UV and NMR spectroscopy as a diastereomeric pair of N7-(2,3,4-trihydroxybutan-1-yl)-guanines. Exposure of dGuo nucleotides to RR/SS DEB (also referred to as dl DEB) followed by thermal depurination resulted in a single product coeluting with the BDE product 1. If the reaction mixture of BDE and 5'-dGMP was analyzed by HPLC before hydrolysis of the glycosidic bond, four major nucleotide alkylation products (A, B, C and D) with identical UV sepectra were detected. The products were isolated and hydrolyzed, after which A and C coeluted with product 1 and B and D coeluted with the product 2. The major adduct of DEB-exposed 5'-dGMP was N7-(2-hydroxy-3,4-epoxy-1-yl)-dGMP (product E). A 32P-post-labeling assay was used to detect BDE- and DEB-derived N7-dGMP adducts in DNA. Levels of adducts increased with a dose of BDE and DEB and exhibited a half life of 30 +/- 3 (r = 0.98) and 31 +/- 4 h (r = 0.95), respectively. Incubation of DEB-modified DNA at 37 degrees C at neutral pH for up to 142 h did not lead to an increase of N7-(2,3,4-trihydroxybutan-1-yl)-dGMP in the DNA. These observations led to the conclusion that the N7-(2,3, 4-trihydroxybutan-1-yl)-dGMP adducts in DNA can be used as a marker of BDE exposure and that N7-(2-hydroxy-3,4-epoxy-1-yl)-dGMP adducts are related to DEB exposure. Dose-related levels of BDE- and DEB-derived adducts were detected in lungs of mice inhaling butadiene. Most of the N7-dGMP adducts (73%; product D) were derived from the 2R-diol-3S-epoxide of 1,3-butadiene. The data presented in this paper indicate that in vivo, 98% of N7-dGMP alkylation after BD exposure is derived from BDE, and approximately 2% of the adducts were derived from DEB and BMO.

Animals↗

PubMed1997

Germ cell mutagenicity of three metabolites of 1,3-butadiene in the rat: induction of spermatid micronuclei by butadiene mono-, di-, and diolepoxides in vivo.

Three metabolites of the industrial chemical 1,3-butadiene (BD), namely butadiene monoepoxide (BMO, 3,4-epoxy-1-butene), diepoxide (DEB, 1,2;3,4-diepoxybutane), and diolepoxide (DE, 3,4- epoxybutane-1,2-diol) were studied for germ cell mutagenicity using the rat spermatid micronucleus (MN) test. All three epoxides increased slightly, but significantly, the frequency of spermatid MN. The most sensitive stage to the action of BMO and DEB was preleptotene (meiotic S phase) harvested at 18-day time intervals after treatment. The dose-response for BMO followed a second order curve at this time interval, with maximum MN induction at the dose of 186 mumol/kg and lower induction of higher doses. Late stages of the meiotic prophase (late pachytene-diplotene-diakinesis) also showed some sensitivity to the three epoxides. Stem cell spermatogonia were affected by DEB as observed by a slight induction of spermatid micronuclei 50 days after treatment. No clear cytotoxic effects were observed by measuring testicular weight or cell numbers of seminiferous epithelial stage 1 18 days after the treatments. DEB at the dose 387 mumol/kg caused a slight inhibition of spermatogonial DNA synthesis in stage I and a delay of meiotic DNA replication observed in stage XII 72 hr after treatment. Since BMO is able to induce spermatid MN in the rat, the present results, together with previous data, indicate that rat bone marrow MN results that are negative for both BD and BMO cannot directly predict mutagenicity in male germ cells. The results also emphasize that tissue; species, and strain-specific differences in metabolism have to be taken into account when the genetic risks of human butadiene exposure are evaluated. The results support the conclusion that 1,3-butadiene is a germ cell mutagen-possibly also in humans.

Animals↗

PubMed2002

Photofragment translational spectroscopy of 1,3-butadiene and 1,3-butadiene-1,1,4,4-d(4) at 193 nm.

The photodissociation dynamics of 1,3-butadiene at 193 nm have been investigated with photofragment translational spectroscopy coupled with product photoionization using tunable VUV synchrotron radiation. Five product channels are evident from this study: C(4)H(5) + H, C(3)H(3) + CH(3), C(2)H(3) + C(2)H(3), C(4)H(4) + H(2), and C(2)H(4) + C(2)H(2). The translational energy (P(E(T))) distributions suggest that these channels result from internal conversion to the ground electronic state followed by dissociation. To investigate the dissociation dynamics in more detail, further studies were carried out using 1,3-butadiene-1,1,4,4-d(4). Branching ratios were determined for the channels listed above, as well as relative branching ratios for the isotopomeric species produced from 1,3-butadiene-1,1,4,4-d(4) dissociation. C(3)H(3) + CH(3) is found to be the dominant channel, followed by C(4)H(5) + H and C(2)H(4) + C(2)H(2), for which the yields are approximately equal. The dominance of the C(3)H(3) + CH(3) channel shows that isomerization to 1,2-butadiene followed by dissociation is facile.

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