title: The metabolism and molecular toxicology of chloroprene.
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.
authors.affiliation: Syngenta Central Toxicology Laboratory, Alderley Park, Macclesfield SK10 4TJ, UK.
authors.forename: Tony
authors.initials: T
authors.lastname: Munter
authors.forename: Lisa
authors.initials: L
authors.lastname: Cottrell
authors.forename: Rikas
authors.initials: R
authors.lastname: Ghai
authors.forename: Bernard T
authors.initials: BT
authors.lastname: Golding
authors.forename: William P
authors.initials: WP
authors.lastname: Watson
mesh_terms: D000818:Animals; D002737:Chloroprene / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity*; D004247:DNA / Q000378:metabolism; D018736:DNA Adducts / Q000378:metabolism; D004851:Epoxide Hydrolases / Q000378:metabolism; D005027:Ethylene Oxide / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis / Q000187:drug effects; D008658:Inactivation, Metabolic; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D009705:Nucleosides / Q000737:chemistry / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D051381:Rats
chemical_list: D018736:DNA Adducts; D009705:Nucleosides; D002737:Chloroprene; D004247:DNA; D004851:Epoxide Hydrolases; D005978:Glutathione; D005027:Ethylene Oxide