Contribution of direct solvent injury to the dose-dependent kinetics of trichloroethylene: Portal vein administration to rats

Presystemic elimination of trichloroethylene (TCE), a common contaminant of drinking water, has been shown by Lee et al. (Toxicol. Appl. Pharmacol. 13 9, 262-271, 1996) to be inversely related to dose. When relatively high dos es were administered to rats,ia the portal vein (PV), first-pass hepatic ex traction became negligible. This phenomenon could result not only from meta bolic saturation, but from suicidal destruction of cytochromes P450 and hep atocellular injury as well The objectives of the current investigation were to: (a) clarify the relative roles of P450 depletion and hepatocellular to xicity in the apparent cessation of hepatic elimination of TCE in animals g iven relatively high doses of TCE via the PV; and (b) investigate mechanism (s) of hepatocellular injury under such exposure conditions. TCE (16 and 64 mg/kg body weight (bw) was incorporated into a 5% aqueous Alkamuls emulsio n and injected via an indwelling jugular vein (JV) or PV cannula into male Sprague-Dawley rats. Some animals received 73.5 mu mol/kg of p-nitrophenol (PNP), a competitive metabolic inhibitor of TCE, through the PV cannula 3 m in before TCE. Administration of TCE via the PV resulted in deposition of r elatively high levels of TCE in the liver. PV dosing resulted in lower tota l hepatic P450 levels than did JV dosing. PV dosing produced marked elevati ons of cytoplasmic enzymes in serum, but JV dosing did not. Decreases in he patic P450 were not selective for cytochrome P4502E1. Histological examinat ion of the liver of PV-dosed rats revealed periportal rather than centrilob ular necrosis. PNP pretreatment failed to prevent the increase in serum enz ymes, decrease in hepatic P450 content, and hepatic necrosis following PV T CE. It is concluded that PV injection of bolus doses of TCE greater than or equal to 16 mg/kg causes liver injury within minutes in rats, primarily th rough direct solvent action on hepatocellular membranes rather than by P450 -mediated effects. This liver damage likely plays a modest role in reducing the liver's capacity to metabolize high PV doses of TCE. (C) 2000 Academic Press.