skip to main content

SciTech ConnectSciTech Connect

Title: Metabolism and disposition of 1-bromopropane in rats and mice following inhalation or intravenous administration

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-{sup 13}C]1-BrP and [1-{sup 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{sub 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 {sup 14}CO{sub 2} (10-30%). For rats, but not mice, the percentage of the dose exhaled as VOCmore » increased between the mid ({approx} 50%) and high ({approx} 71%) dose groups; while the percentage of the dose exhaled as {sup 14}CO{sub 2} decreased (19 to 10%). The molar ratio of exhaled {sup 14}CO{sub 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. [{sup 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 [{sup 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_arrow}30%), exhaled as {sup 14}CO2 ({down_arrow}80%), or retained in liver ({down_arrow}90%), with a concomitant increase in radioactivity expired as VOC ({up_arrow}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.« less
Authors:
 [1] ;  [2] ;  [2] ;  [2] ;  [2] ;  [2] ;  [2] ;  [2] ;  [2] ;  [3] ;  [2]
  1. Department of Drug Metabolism and Disposition, RTI International, Research Triangle Park, NC 27709 (United States). E-mail: cegarner@rti.org
  2. Department of Drug Metabolism and Disposition, RTI International, Research Triangle Park, NC 27709 (United States)
  3. National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 (United States)
Publication Date:
OSTI Identifier:
20850390
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 215; Journal Issue: 1; Other Information: DOI: 10.1016/j.taap.2006.01.010; PII: S0041-008X(06)00034-2; Copyright (c) 2006 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ALANINES; BROMIDES; CARBON 13; CARBON 14; CYSTEINE; FECES; GLUTATHIONE; HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY; INHALATION; LIVER; METABOLISM; METABOLITES; MICE; NUCLEAR MAGNETIC RESONANCE; PROPANOLS; RADIOACTIVITY; RADIOCHROMATOGRAPHY; RATS; URINE