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Citation
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HERO ID
576501
Reference Type
Journal Article
Title
The metabolism and molecular toxicology of chloroprene
Author(s)
Munter, T; Cottrell, L; Ghai, R; Golding, BT; Watson, WP
Year
2007
Is Peer Reviewed?
Yes
Journal
Chemico-Biological Interactions
ISSN:
0009-2797
EISSN:
1872-7786
Publisher
ELSEVIER IRELAND LTD
Location
CLARE
Book Title
Chem Biol Interact.
Volume
166
Issue
1-3
Page Numbers
323-331
Language
English
PMID
16870169
DOI
10.1016/j.cbi.2006.05.017
Web of Science Id
WOS:000246096600036
URL
https://search.proquest.com/docview/20372585?accountid=171501
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Abstract
Chloroprene (2-chloro-1,3-butadiene, 1) is oxidised by cytochrome P450 enzymes in mammalian liver microsomes to several metabolites, some of which are reactive towards DNA and are mutagenic. Much less of the metabolite (1-chloroethenyl)oxirane (2a/2b) was formed by human liver microsomes compared with microsomes from Sprague-Dawley rats and B6C3F1 mice. Epoxide (2a/2b) was a substrate for mammalian microsomal epoxide hydrolases, which showed preferential hydrolysis of the (S)-enantiomer (2b). The metabolite 2-chloro-2-ethenyloxirane (3a/3b) was rapidly hydrolysed to 1-hydroxybut-3-en-2-one (4) and in competing processes rearranged to 1-chlorobut-3-en-2-one (5) and 2-chlorobut-3-en-1-al (6). The latter compound isomerised to (Z)-2-chlorobut-2-en-1-al (7). In microsomal preparations from human, rat and mouse liver, compounds 4, 5 and 7 were conjugated by glutathione both in the absence and presence of glutathione transferases. There was no evidence for the formation of a chloroprene diepoxide metabolite in any of the microsomal systems. The major adducts from the reaction of (1-chloroethenyl)oxirane (2a/2b) with calf thymus DNA were identified as N7-(3-chloro-2-hydroxy-3-buten-1-yl)-guanine (20) and N3-(3-chloro-2-hydroxy-3-buten-1-yl)-2'-deoxyuridine (23), with the latter being derived by alkylation at N-3 of 2'-deoxycytidine, followed by deamination. Adducts in DNA were identified by comparison with those derived from individual deoxyribonucleosides. The metabolite (Z)-2-chlorobut-2-en-1-al (7) formed principally two adducts with 2'-deoxyadenosine which were identified as a pair of diastereoisomers of 3-(2'-deoxy-[beta]-d-ribofuranosyl)-7-(1-hydroxyethyl)-3H-imidazo[2,1-i]purine (25). The chlorine atom of chloroprene thus leads to different intoxication and detoxication profiles compared with those for butadiene and isoprene. The results infer that in vivo oxidations of chloroprene catalysed by cytochrome P450 are more important in rodents, whereas hydrolytic processes catalysed by epoxide hydrolases are more pronounced in humans. The reactivity of chloroprene metabolites towards DNA is important for the toxicology of chloroprene, especially when detoxication is incomplete.
Keywords
Chloroprene; Metabolism; DNA adducts
Conference Name
International Symposium on the Evaluation of Butadiene and Chloroprene Health Risks
Conference Location
Charleston, SC
Tags
IRIS
•
Chloroprene
Cited 2009 Draft
Cited 2010 Final
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