Presystemic elimination of trichloroethylene (TCE), a common contaminant of drinking water, has been shown by Lee et al. (Toxicol. Appl. Pharmacol. 139, 262-271, 1996) to be inversely related to dose. When relatively high doses were administered to rats via the portal vein (PV), first-pass hepatic extraction became negligible. This phenomenon could result not only from metabolic saturation, but from suicidal destruction of cytochromes P450 and hepatocellular injury as well. The objectives of the current investigation were to: (a) clarify the relative roles of P450 depletion and hepatocellular toxicity in the apparent cessation of hepatic elimination of TCE in animals given 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 emulsion and injected via an indwelling jugular vein (JV) or PV cannula into male Sprague-Dawley rats. Some animals received 73.5 μmol/kg of p- nitrophenol (PNP), a competitive metabolic inhibitor of TCE, through the PV cannula 3 min before TCE. Administration of TCE via the PV resulted in deposition of relatively high levels of TCE in the liver. PV dosing resulted in lower total hepatic P450 levels than did JV dosing. PV dosing produced marked elevations of cytoplasmic enzymes in serum, but JV dosing did not. Decreases in hepatic P450 were not selective for cytochrome P4502E1. Histological examination of the liver of PV-dosed rats revealed periportal rather than centrilobular necrosis. PNP pretreatment failed to prevent the increase in serum enzymes, decrease in hepatic P450 content, and hepatic necrosis following PV TCE. It is concluded that PV injection of bolus doses of TCE ≥ 16 mg/kg causes liver injury within minutes in rats, primarily through 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.
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