当前位置： SCI文献检索 > CHEMICAL RESEARCH IN TOXICOLOGY期刊下所有文献 > Identification of novel metabolites of butadiene monoepoxide in rats and mice.

Identification of novel metabolites of butadiene monoepoxide in rats and mice.

Abstract：

:Differences in the metabolism of 1,3-butadiene (Bd) in rats and mice may account for the observed species difference in carcinogenicity. Previous studies of the metabolic fate of Bd have identified epoxide formation as a key metabolic transformation which gives 1, 2-epoxy-3-butene (BMO), although some evidence of aldehyde metabolites is reported. In this study, male Sprague-Dawley rats and male B6C3F1 mice received single doses of [4-14C]BMO at 1, 5, 20, and 50 mg/kg of body weight (0.014, 0.071, 0.286, and 0.714 mmol/kg of body weight). Analysis of urinary metabolites indicated that both species 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-hydroxybut-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-acetyl-L-cystein-S-yl)-1-hydroxybut-3-ene (IId) accounted for 48-64% of urinary radioactivity in rats and 46-54% in mice. The metabolites originating from the R-stereoisomer of BMO (IIc and IId) predominated over those arising from the S-stereoisomer (IIa and IIb) in both species. IIc was formed preferentially 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-dihydroxybutane (Ia), a metabolite derived from hydrolysis of BMO, accounted for 10-17% of the radioactivity in rat and 6-10% in mouse urine. 4-(N-Acetyl-L-cystein-S-yl)-2-hydroxybutanoic acid (Ib), 3-(N-acetyl-L-cystein-S-yl)propan-1-ol (Ic), and 3-(N-acetyl-L-cystein-S-yl)propanoic acid (Id), also derived from the hydrolysis of BMO, were only present in the rat. Metabolites of 1,2,3,4-diepoxybutane (DEB) were not detected after administration of BMO in rat or mouse urine. This study showed both quantitative and qualitative differences in the metabolism of BMO with varying doses and between species. The data aid in the safety evaluation of Bd and contribute to the interpretation of mathematical models developed for quantitative risk assessment and extrapolation of animals to humans.

journal_name

Chem Res Toxicol

journal_title

Chemical research in toxicology

authors

Richardson KA,Peters MM,Megens RH,van Elburg PA,Golding BT,Boogaard PJ,Watson WP,van Sittert NJ

doi

10.1021/tx970175v

subject

Has Abstract

pub_date

1998-12-01 00:00:00

pages

1543-55

issue

eissn

0893-228X

issn

1520-5010

pii

tx970175v

journal_volume

pub_type

杂志文章

在线工具

Identification of novel metabolites of butadiene monoepoxide in rats and mice.