Mechanisms of the dose-dependent kinetics of trichloroethylene: oral bolus dosing of rats.
Trichloroethylene (TCE), a common contaminant of drinking water, is oxidized by high-affinity, low-capacity cytochrome P450 isozymes and subsequently converted to metabolites, some of which are carcinogenic in mice and rats. Although the initial oxidation step is known to be rate-limiting and saturable, the oral dosage-range over which saturation materializes is unclear. One objective of this study was to characterize the dose-dependency of gastrointestinal (GI) absorption of TCE and its kinetics over a wide range of oral bolus doses. A related objective was to investigate cause(s) of the apparent saturation kinetics observed. Cannulas were surgically implanted into a carotid artery and the stomach of male Sprague-Dawley rats. TCE was incorporated into a 5% aqueous Alkamuls emulsion and given in doses of 2 to 1200 mg/kg bw via the stomach tube. Serial blood samples were taken from the arterial cannula for up to 14 h postdosing and analyzed for TCE content by headspace gas chromatography. The rate of GI absorption of TCE diminished as the dosage increased. Pharmacokinetic analysis indicated that TCE was eliminated by capacity-limited hepatic metabolism, with incursion into nonlinear kinetics with bolus doses >/=8 to 16 mg/kg. Effects of p-nitrophenol, a competitive metabolic inhibitor, were manifest at a high, but not at a low TCE dose. Gavage bolus doses as high as 1200 mg/kg did not cause rapid elevation of serum enzyme levels, typical of the solvation of hepatocellular membranes observed after portal vein administration of TCE (Lee et al., Toxicol. Appl. Pharmacol. 163, 000-000, 2000). No evidence of cytochrome P4502E1 (CYP2E1) destruction was seen with oral doses up to 1000 mg/kg. Instead, CYP2E1 activity was induced as early as 1 h postdosing. Induction was maximal at 12 h, then returned toward controls during the next 12 h. Pretreatment with cycloheximide did not reduce CYP2E1 activity in rats given 432 or 1000 mg TCE/kg, suggesting that binding of TCE to CYP2E1 may stabilize the isozyme. Metabolic saturation, in concert with relatively slow GI absorption, are responsible for the prolonged elevation of blood TCE levels in rats given high TCE doses, while suicidal inactivation of CYP2E1 and hepatocellular injury apparently play little role.
Lee
K M
KM
Toxicology Northwest, M.S. K4-10, Battelle, Richland, Washington 99352, USA.
Muralidhara
S
S
White
C A
CA
Bruckner
J V
JV
D000284:Administration, Oral; D000818:Animals; D003513:Cycloheximide / Q000494:pharmacology; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D008099:Liver / Q000187:drug effects; D008297:Male; D009596:Nitrophenols / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014241:Trichloroethylene / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity
D009596:Nitrophenols; D014241:Trichloroethylene; D003513:Cycloheximide; D019392:Cytochrome P-450 CYP2E1; C024836:4-nitrophenol