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CYP2E1-Catalyzed Oxidation Contributes to the Sperm Toxicity of 1-Bromopropane in Mice¹

RTI International,⁴ Research Triangle Park, North Carolina 27709 National Institute of Environmental Health Sciences,⁵ Research Triangle Park, North Carolina 27709

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 [1,2,3-¹³C]-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.

epididymis, male reproductive tract, sperm, sperm motility and transport, toxicology

³Current address: Drug Metabolism and Pharmacokinetics, Cancer and Infection, Discovery Research, AstraZeneca, 35 Gatehouse Rd., Waltham, MA 02451.

¹This research was supported by the Intramural Research Program of the National Institutes of Health/National Institute of Environmental Health Sciences.

Correspondence: ²C. Edwin Garner, Department of Drug Metabolism and Pharmacokinetics, RTI International, Research Triangle Park, NC 27709. FAX: 781 839 4380; e-mail: cegarner{at}rti.org