title: Metabolism and disposition of 1-bromopropane in rats and mice following inhalation or intravenous administration.
abstract: Workplace exposure to 1-bromopropane (1-BrP) can potentially occur during its use in spray adhesives, fats, waxes, and resins. 1-BrP may be used to replace ozone depleting solvents, resulting in an increase in its annual production in the US, which currently exceeds 1 million pounds. The potential for human exposure to 1-BrP and the reports of adverse effects associated with potential occupational exposure to high levels of 1-BrP have increased the need for the development of biomarkers of exposure and an improved understanding of 1-BrP metabolism and disposition. In this study, the factors influencing the disposition and biotransformation of 1-BrP were examined in male F344 rats and B6C3F1 mice following inhalation exposure (800 ppm) or intravenous administration (5, 20, and 100 mg/kg). [1,2,3-(13)C]1-BrP and [1-(14)C]1-BrP were administered to enable characterization of urinary metabolites using NMR spectroscopy, LC-MS/MS, and HPLC coupled radiochromatography. Exhaled breath volatile organic chemicals (VOC), exhaled CO(2), urine, feces, and tissues were collected for up to 48 h post-administration for determination of radioactivity distribution. Rats and mice exhaled a majority of the administered dose as either VOC (40-72%) or (14)CO(2) (10-30%). For rats, but not mice, the percentage of the dose exhaled as VOC increased between the mid ( approximately 50%) and high ( approximately 71%) dose groups; while the percentage of the dose exhaled as (14)CO(2) decreased (19 to 10%). The molar ratio of exhaled (14)CO(2) to total released bromide, which decreased as dose increased, demonstrated that the proportion of 1-BrP metabolized via oxidation relative to pathways dependent on glutathione conjugation is inversely proportional to dose in the rat. [(14)C]1-BrP equivalents were recovered in urine (13-17%, rats; 14-23% mice), feces (<2%), or retained in the tissues and carcass (<6%) of rats and mice administered i.v. 5 to 100 mg/kg [(14)C]1-BrP. Metabolites characterized in urine of rats and mice include N-acetyl-S-propylcysteine, N-acetyl-3-(propylsulfinyl)alanine, N-acetyl-S-(2-hydroxypropyl)cysteine, 1-bromo-2-hydroxypropane-O-glucuronide, N-acetyl-S-(2-oxopropyl)cysteine, and N-acetyl-3-[(2-oxopropyl)sulfinyl]alanine. These metabolites may be formed following oxidation of 1-bromopropane to 1-bromo-2-propanol and bromoacetone and following subsequent glutathione conjugation with either of these compounds. Rats pretreated with 1-aminobenzotriazole (ABT), a potent inhibitor of P450 excreted less in urine (down 30%), exhaled as (14)CO2 (down 80%), or retained in liver (down 90%), with a concomitant increase in radioactivity expired as VOC (up 52%). Following ABT pretreatment, rat urinary metabolites were reduced in number from 10 to 1, N-acetyl-S-propylcysteine, which accounted for >90% of the total urinary radioactivity in ABT pretreated rats. Together, these data demonstrate a role for cytochrome P450 and glutathione in the dose-dependent metabolism and disposition of 1-BrP in the rat.
authors.affiliation: Department of Drug Metabolism and Disposition, RTI International, Research Triangle Park, NC 27709, USA. cegarner@rti.org
authors.forename: C E
authors.initials: CE
authors.lastname: Garner
authors.forename: S C J
authors.initials: SC
authors.lastname: Sumner
authors.forename: J G
authors.initials: JG
authors.lastname: Davis
authors.forename: J P
authors.initials: JP
authors.lastname: Burgess
authors.forename: Y
authors.initials: Y
authors.lastname: Yueh
authors.forename: J
authors.initials: J
authors.lastname: Demeter
authors.forename: Q
authors.initials: Q
authors.lastname: Zhan
authors.forename: J
authors.initials: J
authors.lastname: Valentine
authors.forename: A R
authors.initials: AR
authors.lastname: Jeffcoat
authors.forename: L T
authors.initials: LT
authors.lastname: Burka
authors.forename: J M
authors.initials: JM
authors.lastname: Mathews
mesh_terms: D000818:Animals; D002851:Chromatography, High Pressure Liquid; D006842:Hydrocarbons, Brominated / Q000008:administration & dosage / Q000493:pharmacokinetics; D007262:Infusions, Intravenous; D019570:Inhalation Exposure; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D006842:Hydrocarbons, Brominated; C118559:1-bromopropane