Species and sex-dependent toxicokinetics of 1-bromopropane: the role of hepatic cytochrome P450 oxidation and glutathione (GSH).
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.
RTI International, Research Triangle Park , NC , USA and.
C Edwin
CE
Garner
X
X
Yu
D000280:Administration, Inhalation; D000818:Animals; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System; D004305:Dose-Response Relationship, Drug; D005260:Female; D005978:Glutathione / Q000378:metabolism*; D006207:Half-Life; D006842:Hydrocarbons, Brominated / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity; D008658:Inactivation, Metabolic; D019570:Inhalation Exposure; D007275:Injections, Intravenous; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008815:Mice, Inbred Strains; D011916:Rats, Inbred F344; D012737:Sex Factors; D013045:Species Specificity
D065607:Cytochrome P-450 Enzyme Inhibitors; D006842:Hydrocarbons, Brominated; D003577:Cytochrome P-450 Enzyme System; D005978:Glutathione; C118559:1-bromopropane
1-Bromopropane; P4502E1; glutathione; toxicokinetics