Comparison of the biotransformation of 1,3-butadiene and its metabolite, butadiene monoepoxide, by hepatic and pulmonary tissues from humans, rats and mice

Abstract

1,3-Butadiene (BD), a widely used monomer in the production of synthetic rubber and other resins, is one of the 189 hazardous air pollutants identified in the 1990 Clean Air Act Amendments. BD induces tumors at multiple organ sites in B6C3F1 mice and Sprague-Dawley rats; mice are much more susceptible to the carcinogenic action of BD than are rats. Previous in vivo studies have indicated higher circulating blood levels of butadiene monoepoxide (BMO), a potential carcinogenic metabolite of BD, in mice compared to rats, suggesting that species differences in the metabolism of BD may be responsible for the observed differences in carcinogenic susceptibility. The metabolic fate of BD in humans is unknown. The objective of these studies was to quantitate in vitro species differences in the oxidation of BD and BMO by cytochrome P450-dependent monooxygenases and the inactivation of BMO by epoxide hydrolases and glutathione S-transferases using microsomal and cytosolic preparations of livers and lungs obtained from Sprague-Dawley rats, B6C3F1 mice and humans. Maximum rates for BD oxidation (Vmax) were highest for mouse liver microsomes (2.6 nmol/mg protein/min) compared to humans (1.2) and rats (0.6). The Vmax for BD oxidation by mouse lung microsomes was similar to that of mouse liver but greater than 10-fold higher than the Vmax for the reaction in human or rat lung microsomes. Correlation analysis revealed that P450 2E1 is the major P450 enzyme responsible for oxidation of BD to BMO. Only mouse liver microsomes displayed quantifiable rates for metabolism of BMO to butadiene diepoxide (Vmax = 0.2 nmol/mg protein/min), a known rodent carcinogen. Human liver microsomes displayed the highest rate of BMO hydrolysis by epoxide hydrolases. The Vmax in human liver microsomes ranged from 9 to 58 nmol/mg protein/min and was at least 2-fold higher than the Vmax observed in mouse and rat liver microsomes. The Vmax for glutathione S-transferase-catalyzed conjugation of BMO with glutathione was highest for mouse liver cytosol (500 nmol/mg protein/min) compared to human (45) or rat (241) liver cytosol. In general, the KMs for the detoxication reactions were 1000-fold higher than the KMs for the oxidation reaction. Because of the low solubility of the BD and the relatively high KM for oxidation, it is likely that the Vmax/KM ratio will be important for BD and BMO metabolism in vivo. In vivo clearance constants were calculated from in vitro data for BD oxidation and BMO oxidation, hydrolysis and GSH conjugation.(ABSTRACT TRUNCATED AT 400 WORDS)

Biomonitoring of 1,3-butadiene and related compounds.

“…This study extended the findings of Sabourin et al (36) by showing that humans are similar to the monkey in that M1 is the predominant metabolite in urine. The findings are consistent with the higher ratio of M1/(M1 + M2) in humans compared to rats or mice and the higher rate of epoxide hydrolase activity in the livers of humans compared to rats and mice (i.e., humans > rats > mice) (32). The average values of M1 for exposed, intermediately exposed, nonexposed, and outside control employees were 3200 + 1600, 1390 ± 550, 630 ± 190, and 320 + 70 ng/ml (mean ± SE), respectively.…”

“…Diepoxybutane also induces genetic damage in vitro in mammalian cells (Chinese hamster ovary cells and human peripheral blood lymphocytes) at lower concentrations than epoxybutene (27,28 appear to play major roles in the overall metabolism of butadiene: cytochrome P450 monooxygenase, epoxide hydrolase, and glutathione (GSH) S-transferase. The metabolic activation of butadiene proceeds by cytochrome P450-mediated oxidation to epoxybutene (29)(30)(31)(32)(33). Cytochrome P4502E1 is the major P450 isozyme for the metabolism of butadiene (32), although P4502A6 can also oxidize butadiene to epoxybutene (34).…”

“…The metabolic activation of butadiene proceeds by cytochrome P450-mediated oxidation to epoxybutene (29)(30)(31)(32)(33). Cytochrome P4502E1 is the major P450 isozyme for the metabolism of butadiene (32), although P4502A6 can also oxidize butadiene to epoxybutene (34). Epoxybutene is metabolized further by cytochrome P450 to diepoxybutane, and recent studies indicate that both P4502E1 and P4503A4 catalyze this oxidation step (35).…”

“…Epoxybutene is metabolized further by cytochrome P450 to diepoxybutane, and recent studies indicate that both P4502E1 and P4503A4 catalyze this oxidation step (35). Epoxide hydrolase and GSH S-transferase are the two enzymes responsible for the metabolic inactivation of epoxybutene (32,(36)(37)(38) and diepoxybutane (39,40 (32). Additionally, mice have a faster rate of GSH conjugation with epoxybutene in lung tissues than rats or humans, and humans have faster rates of epoxybutene hydrolysis by epoxide hydrolase compared to rats or mice (32).…”

“…Epoxide hydrolase and GSH S-transferase are the two enzymes responsible for the metabolic inactivation of epoxybutene (32,(36)(37)(38) and diepoxybutane (39,40 (32). Additionally, mice have a faster rate of GSH conjugation with epoxybutene in lung tissues than rats or humans, and humans have faster rates of epoxybutene hydrolysis by epoxide hydrolase compared to rats or mice (32). The rate of cytochrome P450-mediated epoxidation of epoxybutene to diepoxybutane in liver microsomes is highest in mice, while rats and humans have a similar rate (35).…”