In Vitro Metabolism of Chloroprene:  Species Differences, Epoxide Stereochemistry and a De-chlorination Pathway

Chloroprene (1) was metabolized by liver microsomes from Sprague−Dawley rats, Fischer 344 rats, B6C3F1 mice, and humans to the monoepoxides, (1-chloro-ethenyl)oxirane (5a/5b), and 2-chloro-2-ethenyloxirane (4a/4b). The formation of 4a/4b was inferred from the identification of their degradation prod...

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Bibliographic Details
Published in:Chemical research in toxicology 2001-11, Vol.14 (11), p.1552-1562
Main Authors: Cottrell, Lisa, Golding, Bernard T, Munter, Tony, Watson, William P
Format: Article
Language:English
Subjects:
Animals
chloroprene
Chloroprene - chemistry
Chloroprene - metabolism
Epoxy Compounds - chemistry
Female
Gas Chromatography-Mass Spectrometry
Humans
Male
Mice
Mice, Inbred Strains
Microsomes, Liver - drug effects
Rats
Rats, Inbred F344
Rats, Sprague-Dawley
Reference Values
Stereoisomerism
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Summary:Chloroprene (1) was metabolized by liver microsomes from Sprague−Dawley rats, Fischer 344 rats, B6C3F1 mice, and humans to the monoepoxides, (1-chloro-ethenyl)oxirane (5a/5b), and 2-chloro-2-ethenyloxirane (4a/4b). The formation of 4a/4b was inferred from the identification of their degradation products. With male Sprague−Dawley and Fischer 344 rat liver microsomes, there was a ca. 3:2 preference for the formation of (R)-(1-chloroethenyl)oxirane (5a) compared to the (S)-enantiomer (5b). A smaller but distinct enantioselectivity in the formation of (S)-(1-chloro-ethenyl)oxirane occurred with liver microsomes from male mouse (R:S, 0.90:1) or male human (R:S, 0.86:1). 2-Chloro-2-ethenyloxirane was very unstable in the presence of the microsomal mixture and was rapidly converted to 1-hydroxybut-3-en-2-one (11) and 1-chlorobut-3-en-2-one (12). An additional rearrangement pathway of 2-chloro-2-ethenyloxirane gave rise to 2-chlorobut-3-en-1-al (14) and 2-chlorobut-2-en-1-al (15). Further reductive metabolism of these metabolites occurred to form 1-hydroxybutan-2-one (17) and 1-chlorobutan-2-one (18). In the absence of an epoxide hydrolase inhibitor, the microsomal incubations converted (1-chloroethenyl)oxirane to 3-chlorobut-3-ene-1,2-diol (21a/21b). When microsomal incubations were supplemented with glutathione, 1-hydroxybut-3-en-2-one was not detected because of its rapid conjugation with this thiol scavenger.
ISSN:0893-228X
1520-5010
DOI:10.1021/tx0155404