Identification of novel metabolites of butadiene monoepoxide in rats and mice

Differences in the metabolism of 1,3-butadiene (Bd) in rats and mice may ac count for the observed species difference in carcinogenicity. Previous stud ies of the metabolic fate of Ed have identified epoxide formation as a key metabolic transformation which gives 1,2-epoxy-3-butene (BMO), although som e evidence of aldehyde metabolites is reported. In this study, male Sprague -Dawley rats and male B6C3F1 mice received single doses of [4-C-14]BMO at 1 , 5, 20, and 50 mg/kg of body weight (0.014, 0.071, 0.286, and 0.714 mmol/k g of body weight). Analysis of urinary metabolites indicated that both spec ies preferentially metabolize BMO by direct reaction with GSH when given by ip administration. The excretion of (R)-2-(N-acetyl-L-cystein-S-yl)-1-hydr oxybut-3-ene (IIa), 1-(N-acetyl-L-cystein-S-yl)-2-(S)-hydroxybut-3-ene (IIb ), 1-(N-acetyl-L-cystein-S-yl)-2-(R)-hydroxybut-3-ene (IIc), and (S)-2-(N-a cetyl-L-cystein-S-yl)- 1-hydroxybut-3-ene (IId) accounted for 48-64% of uri nary radioactivity in rats and 46-54% in mice. The metabolites originating from the R-stereoisomer of BMO (IIc and IId) predominated over those arisin g from the S-stereoisomer (IIa and IIb) in both species. IIc was formed pre ferentially in mice and IId in rats. The corresponding mercaptoacetic acids , S-(1-hydroxybut-3-en-2-yl)mercaptoacetic acid (IIf) and S-(2-hydroxybut-3 -en-1-yl)mercaptoacetic acid (IIg), were identified only in mouse urine (ca . 20% of the recovered radioactivity,, 4-(N-Acetyl-L-cystein-S-yl)- 1,2-dih ydroxybutane (Ia), a metabolite derived from hydrolysis of BMO, accounted f or 10-17% of the radioactivity in rat and 6-10% in mouse urine. 4-(N-Acetyl -L-cystein-S-yl)-2-hydroxybutanoic acid (1b), 3-(N-acetyl-L-cystein-S-yl)pr opan-1-ol (Ic), and 3-(N-acetyl-L-cystein-S-yl)propanoic acid (Id:). also d erived from the hydrolysis of RR IO, were only present in the rat. Metaboli tes of 1,2,3,4-diepoxybutane (DEB) were not detected after administration o f BMO in rat or mouse urine. This study showed both quantitative and qualit ative differences in the metabolism of BMO with varying doses and between s pecies. The data aid in the safety evaluation of Ed and contribute to the i nterpretation of mathematical models developed for quantitative risk assess ment and extrapolation of animals to humans.