Species and Sex-Dependent Toxicokinetics of 1-Bromopropane: The Role of Hepatic Cytochrome P450 Oxidation and Glutathione (GSH)

Details

• Personal Author:
  Garner CE ; Yu X
• Description:
  1. The objectives of the current studies were to evaluate the factors influencing the toxicokinetics of 1-bromopropane (1-BP) in rodents after intravenous (IV) and inhalation exposure. 2. F-344 rats were administered 1-BP via IV bolus injection at 5 and 20 mg/kg and blood concentration determined versus time. F-344 rats and B6C3F1 mice were also exposed to starting inhalation concentrations 70, 240, 800 and 2700 ppm 1-BP in a closed gas uptake system and chamber 1-BP levels were monitored for 6 h. Plasma bromide concentrations were determined to estimate total metabolized dose. Rats were pretreated with chemical inhibitors of cytochrome P450 and glutathione (GSH) synthesis, prior to exposure to 1-BP at 800 ppm within inhalation chambers. 3. Systemic clearance of 1-BP in rat was rapid and decreased with increasing dose. As inhalation chamber concentration of 1-BP increased, the terminal elimination rates decreased. Half-life of 1-BP in rats following inhibition of P450 (9.6 h) or depletion of GSH (4.1 h) increased relative to controls (2.0 h) at 800 ppm. The percentage of 1-BP metabolized decreased with increasing inhalation exposure. Hepatic levels of GSH were significantly lowered regardless of the exposure level in both rats and mice. Chamber concentration-time curves were fit to a two compartment model which was used to estimate metabolic rate constants. 4. These data suggest that in rat, 1-BP clearance is saturable and that elimination is highly dependent on both P450 and GSH-dependent metabolism. This investigation in rodents may provide an understanding of interspecies differences in toxicokinetics and eventually aid translation of animal studies to human risk assessment. [Description provided by NIOSH]
• Subjects:
  Animals Occupational Health Safety
• Keywords:
  1-Bromopropane Animal Studies Author Keywords: 1-Bromopropane Biological Effects Dose Response Glutathione P4502E1 Toxic Effects Toxicokinetics
• ISSN:
  0049-8254
• Document Type:
  Text
• Funding:
  Grant
• Genre:
  Journal Article
• Place as Subject:
  Georgia ; New Mexico ; North Carolina ; OSHA Region 4 ; OSHA Region 6
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  44
• Issue:
  7
• NIOSHTIC Number:
  nn:20053962
• Citation:
  Xenobiotica 2014 Jul; 44(7):644-656
• Contact Point Address:
  C. Edwin Garner, Metabolism and Pharmacokinetics, Lovelace Respiratory Research Institute, Albuquerque, New Mexico, USA
• Email:
  Halifax_garner@yahoo.com
• CAS Registry Number:
  1-Bromopropane (CAS RN 106-94-5)
• Federal Fiscal Year:
  2014
• Performing Organization:
  University of Georgia, Athens
• Peer Reviewed:
  True
• Start Date:
  20130901
• Source Full Name:
  Xenobiotica
• End Date:
  20160831
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:51b4c70c58d066bd117af3a9d015a44ea5fbc2845d2b7eccefe2076edf9d0a1e595fd333cd63cfff7446bbe0cbc3800a48cc018640c41b1f24e98461e604b0f1
• Download URL:
  https://stacks.cdc.gov/view/cdc/216618/cdc_216618_DS1.pdf
• File Type:
  [PDF - 1.97 MB ]