Mechanism of Trichloroethylene-Induced Elevation of Individual Serum Bile Acids: II. In Vitro and in Vivo Interference by Trichloroethylene with Bile Acid Transport in Isolated Rat Hepatocytes

Abstract

The effects of trichloroethylene (TRI) on bile acid transport in isolated rat hepatocytes have been studied using doses ranging from 0.5 to 4.0 μl/flask and a 20-min equilibration period. It was found that TRI caused a dose-related suppression of initial rates of uptake of cholic acid (CA) and taurocholic acid (TC) with no significant effect on enzyme leakage and intracellular potassium ion contents. Accumulation over 30 min for each of those two bile acids was also inhibited. A noncompetitive inhibition of bile acid uptake was shown as indicated by a decrease in maximum velocity ( V max) and unchanged Michaelis constant ( K m ). Thirty minutes after cessation of TRI exposure in vitro the uptake of bile acids had gradually returned to normal levels. No significant interference of efflux was found in cells preloaded with either CA or TC. After dosing rats with 1 mmol/kg TRI in vivo the inhibition of uptake of CA and TC by subsequently isolated hepatocytes was not detected until 4 hr. By 16 hr uptake had returned to normal. The accumulation of bile acids was also suppressed at 4 and 8 hr. The inhibition of uptake after in vivo treatment was also noncompetitive. The data are consistent with the reversible increase of serum bile acids (SBA) in experimental animals after exposure to TRI. Furthermore, they support the contention that it is an interference with bile acid uptake, rather than actual cell damage, that is responsible for TRI induced increases in SBA. Thus, the changes in SBA seem to be the result of interference with a physiological process rather than an event associated with significant pathological consequences.