title: Detoxication pathways involving glutathione and epoxide hydrolase in the in vitro metabolism of chloroprene.
abstract: Chloroprene (2-chloro-1,3-butadiene, 1) is an important industrial chemical, which is carcinogenic in experimental animals and possibly in humans. It is metabolized to the monoepoxides, 2-chloro-2-ethenyloxirane (2a,b) and (1-chloroethenyl)oxirane (3a,b), together with electrophilic chlorinated aldehydes and ketones. This study has investigated the detoxication of these chloroprene metabolites in vitro by glutathione (GSH) and epoxide hydrolase (EH) in liver microsomes from Sprague-Dawley rats, B6C3F1 mice, and humans. In incubations of chloroprene with liver microsomes containing GSH, several GSH conjugates were identified. These were 1-hydroxy-4-(S-glutathionyl)butan-2-one (13), 1,4-bis-(S-glutathionyl)butan-2-one (15), and (Z)-2-(S-glutathionyl)but-2-en-1-al (16). A fourth GSH conjugate was identified as either 2-chloro-3-hydroxy-4-(S-glutathionyl)butene (12a,b) or 1-chloro-4-(S-glutathionyl)-butan-2-one (14), which were indistinguishable by LC/MS. Structural assignments of metabolites were based on chromatographic and spectroscopic comparisons with synthetic standards. There were significant differences between species in the amounts of 3a,b formed in microsomal incubations, the order being mouse > rat > human. Hydrolysis by microsomal EHs showed a distinct selectivity for S-(1-chloroethenyl)oxirane (3b) resulting in an accumulation of the R-enantiomer; the ratio of the amounts between species was 20:4:1 for mouse:rat:human, respectively.
authors.affiliation: Syngenta Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire, SK10 4TJ, United Kingdom. b.t.golding@ncl.ac.uk
authors.forename: Tony
authors.initials: T
authors.lastname: Munter
authors.forename: Lisa
authors.initials: L
authors.lastname: Cottrell
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*; D002851:Chromatography, High Pressure Liquid; D004851:Epoxide Hydrolases / Q000378:metabolism*; D004852:Epoxy Compounds / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis; D008658:Inactivation, Metabolic; D008099:Liver / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D051379:Mice; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D015394:Molecular Structure; D010084:Oxidation-Reduction; D051381:Rats; D013237:Stereoisomerism
chemical_list: D004852:Epoxy Compounds; D002737:Chloroprene; D004851:Epoxide Hydrolases; D005978:Glutathione