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

Schmidt, Ulrich; Loeser, Edward A.

doi:10.1007/bf00324781

Cited by 62 publications

(34 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recent studies in which BDMO formation was directly measured in vitro revealed that mouse lung microsomes activate butadiene at rates nearly 15 times greater than in rats (55). Lorenz and co-workers (56) also reported that the relative activation of butadiene by mouse lung microsomes was greater than that observed in rat lung, in agreement with studies by Schmidt and Loeser (57). In vitro hepatic activities observed from all of these groups has been greater in the mouse than in the rat.…”

Section: Pharmacokineticssupporting

confidence: 68%

A brief survey of butadiene health effects: a role for metabolic differences.

Birnbaum

1993

Environ Health Perspect

View full text Add to dashboard Cite

1,3-Butadiene is a major monomer in the rubber and plastics industry and is one of the highest-production industrial chemicals in the United States. Although not highly acutely toxic to rodents, inhalation of concentrations as low as 6.25 ppm causes tumors in mice. Butadiene is oncogenic in rats, but much higher exposure concentrations are required than in mice. Chronic toxicity targets the gonads and hematopoetic system. Butadiene is also a potent mutagen and clastogen. Differences in the absorption, distribution, and elimination of butadiene appear to be relatively minor between rats and mice, although mice do retain more butadiene and its metabolites after exposure to the same concentration and have a higher rate of metabolic elimination. Recent studies have demonstrated that major species differences appear to occur in the rate of detoxication of the primary metabolite, 3-epoxybutene (butadiene monoepoxide [BDMO]). Mice have the greatest rate of production of BDMO as compared to other species, but the rate of removal of BDMO appears to be less than in other species. Mice have low levels of epoxide hydrolase; rats have intermediate levels; monkeys and humans appear to have high levels of this detoxifying enzyme. Thus, while only low levels of butadiene exposure may result in an accumulation of BDMO in the mouse, much higher levels would be required to result in an elevation of circulating BDMO in other species. The level of this reactive metabolite may be correlated with the species differences in butadiene sensitivity.

show abstract

Section: Pharmacokineticssupporting

confidence: 68%

A brief survey of butadiene health effects: a role for metabolic differences.

Birnbaum

1993

Environ Health Perspect

View full text Add to dashboard Cite

show abstract

“…Considering these data, epoxide hydrolase seems to have a high capacity for butadiene monoxide which is a substrate with medium affinity. In man for liver microsomes different groups reported Vmax values between 5 and 6800 nmol/(min • mg protein) depending on the substrate (Oesch et al 1974;Glatt et al 1980;Lorenz et al 1984;Mertes et al 1985;Schmidt and Loeser 1985). The relative epoxide hydrolase capacity for butadiene monoxide in our system was therefore low.…”

Section: Liver Microsomesmentioning

confidence: 68%

Enzyme specific kinetics of 1,2-epoxybutene-3 in microsomes and cytosol from livers of mouse, rat, and man

Kreuzer¹,

Kessler²,

Welter³

et al. 1991

Arch Toxicol

View full text Add to dashboard Cite

Kinetics of the metabolism of 1,2-epoxybutene-3 (butadiene monoxide) were investigated in liver fractions of mouse, rat, and man. In these species similar enzyme characteristics were found. In microsomes, no NADPH-dependent metabolism of butadiene monoxide was detectable. Epoxide hydrolase activity was found only in microsomes. The Vmax [nmol butadiene monoxide/(mg protein x min)] was 19 in mouse, 17 in rat, and 14 in man and the apparent Km (mmol butadiene monoxide/l incubate) was 1.5 in mouse. 0.7 in rat, and 0.5 in man. Glutathione S-transferase activity was found in cytosol only, revealing first order kinetics in the measured range. The ratio Vmax/Km [(nmol butadiene monoxide x 1)/(mg protein x min x mmol of butadiene monoxide)] was 15 in mouse, 11 in rat, and 8 in man. The data obtained were used to extrapolate on the total rate of butadiene monoxide metabolism for each species in vivo: it was calculated to be 1.3 times higher in mice and 2.3 times lower in man compared to rats, when corrected for body weight.

show abstract

“…Such a species difference has also been postulated from the in vitro and in vivo data on BU and BMO metabolism (e.g. by Schmidt and Loeser 1985;Bond et al 1986;Dahl et al 1990;Kreuzer et al 1991;Csanfidy et al 1992). The present model adds a more precise quantitative estimate, as respiratory uptake and excretion, distribution in the body, and metabolism of BU as well as BMO is incorporated.…”

Section: Discussionmentioning

confidence: 92%

A physiologically based pharmacokinetic model for butadiene and its metabolite butadiene monoxide in rat and mouse and its significance for risk extrapolation

Johanson

Filser²

1993

Arch Toxicol

View full text Add to dashboard Cite

The gas 1,3-butadiene (BU) is an important industrial chemical and an environmental air pollutant. BU has been shown to be a weak carcinogen in the rat but a potent carcinogen in the B6C3F1 mouse. This species difference makes risk extrapolation to humans difficult and the underlying mechanism should be clarified before meaningful risk extrapolation to humans can be made. One possible explanation for the species differences in cancer response is that there are quantitative species differences in the formation of genotoxic epoxides. To investigate this possibility a physiologically based pharmacokinetic (pbpk) model for BU together with its first reactive metabolite 1,2-epoxybutene-3 (butadiene monoxide, BMO) was developed. Previously reported values on hepatic glutathione (GSH) turnover, depletion of hepatic GSH in rodents exposed to BU, and in vitro metabolic data of BU and BMO were included in the model, which incorporates intrahepatic first-pass hydrolysis of BMO and the ordered sequential, ping-pong mechanism to describe the enzyme kinetics of BMO-GSH conjugation. In vitro studies were carried out to obtain tissue: air partition coefficients of BU and BMO in rat tissue homogenates. The simulated pharmacokinetics of BU, BMO, and GSH agreed with previously published experimental observations in rat and mouse obtained in closed and open chamber experiments. According to the model, the internal dose of BMO (expressed either as the concentration in mixed venous blood or as the area under the concentration-time curve) is approximately 1.6 times higher in the mouse than in the rat for exposure to BU below 1000 ppm. At higher exposure levels, GSH depletion occurs in the mouse, but not in the rat, after about 6-9 h. This GSH depletion results in up to 2-3 times higher internal doses in the mouse than in the rat. The clear but relatively small species differences in body burdens of BMO indicated from our model can only partly explain the marked species difference in cancer response between mice and rats exposed to BU.

show abstract

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

Cited by 62 publications

References 15 publications

A brief survey of butadiene health effects: a role for metabolic differences.

A brief survey of butadiene health effects: a role for metabolic differences.

Enzyme specific kinetics of 1,2-epoxybutene-3 in microsomes and cytosol from livers of mouse, rat, and man

A physiologically based pharmacokinetic model for butadiene and its metabolite butadiene monoxide in rat and mouse and its significance for risk extrapolation

Contact Info

Product

Resources

About