title: CYP2E1-catalyzed oxidation contributes to the sperm toxicity of 1-bromopropane in mice.
abstract: 1-bromopropane (1-BrP) induces dose- and time-dependent reproductive organ toxicity and reduced sperm motility in rodents. The contribution of cytochrome P4502E1 (CYP2E1) to both 1-BrP metabolism and the induction of male reproductive toxicity was investigated using wild-type (WT) and Cyp2e1-/- mice. In gas uptake inhalation studies, the elimination half-life of [1,2,3-(13)C]-1-BrP was longer in Cyp2e1-/- mice relative to WT (3.2 vs. 1.3 h). Urinary metabolites were identified by 13C nuclear magnetic resonance. The mercapturic acid of 1-bromo-2-hydroxypropane (2OHBrP) was the major urinary metabolite in WT mice, and products of conjugation of 1-BrP with glutathione (GSH) were insignificant. The ratio of GSH conjugation to 2-hydroxylation increased 5-fold in Cyp2e1-/- mice relative to WT. After 1-BrP exposure, hepatic GSH was decreased by 76% in WT mice vs. 47% in Cyp2e1-/- mice. Despite a 170% increase in 1-BrP exposure in Cyp2e1-/- vs. WT mice, sperm motility in exposed Cyp2e1-/- mice did not change relative to unexposed matched controls. This suggests that metabolites produced through CYP2E1-mediated oxidation may be responsible for 1-BrP-induced sperm toxicity. Both 1-BrP and 2OHBrP inhibited the motility of sperm obtained from WT mice in vitro. However, only 2OHBrP reduced the motility of sperm obtained from Cyp2e1-/- mice in vitro, suggesting that conversion of parent compound to 2OHBrP within the spermatozoa may contribute, at least in part, to reduced motility. Overall, these data suggest that metabolism of 1-BrP is mediated in part by CYP2E1, and activation of 1BrP via this enzyme may contribute to the male reproductive toxicity of this chemical.
authors.affiliation: RTI International, Research Triangle Park, North Carolina 27709, USA. cegarner@rti.org
authors.forename: C Edwin
authors.initials: CE
authors.lastname: Garner
authors.forename: C
authors.initials: C
authors.lastname: Sloan
authors.forename: S C J
authors.initials: SC
authors.lastname: Sumner
authors.forename: J
authors.initials: J
authors.lastname: Burgess
authors.forename: J
authors.initials: J
authors.lastname: Davis
authors.forename: A
authors.initials: A
authors.lastname: Etheridge
authors.forename: A
authors.initials: A
authors.lastname: Parham
authors.forename: B I
authors.initials: BI
authors.lastname: Ghanayem
mesh_terms: D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000378:metabolism; D000280:Administration, Inhalation; D000818:Animals; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D020719:Glucuronides / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006842:Hydrocarbons, Brominated / Q000008:administration & dosage / Q000633:toxicity; D008658:Inactivation, Metabolic; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D010084:Oxidation-Reduction; D013081:Sperm Motility / Q000187:drug effects; D013094:Spermatozoa / Q000187:drug effects* / Q000378:metabolism; D014556:Urine / Q000502:physiology
chemical_list: C520625:1-bromo-2-propanol-glucuronide; D020719:Glucuronides; D006842:Hydrocarbons, Brominated; C520626:N-acetyl-S-propylcysteine; D019392:Cytochrome P-450 CYP2E1; D005978:Glutathione; D000111:Acetylcysteine; C118559:1-bromopropane