Interference with hepatocellular substrate uptake by 1,1,1-trichloroethane and tetrachloroethylene.

The effects of chlorinated aliphatic hydrocarbon solvent exposure on hepatocellular transport of some model substrates have been investigated. Exposure of isolated hepatocytes to 1,1,1-trichloroethane or tetrachloroethylene resulted in suppression of uptake of taurocholate, ouabain, and 2-aminoisobutyric acid but not CdCl2 or 3-O-methyl-D-glucose. The effect was clearly evident at noncytotoxic concentrations, as indicated by the lack of intracellular enzyme leakage and unaltered intracellular K+ ion concentration. Moreover, the ultrastructure of solvent-exposed hepatocytes was similar to that of control cells, except for a reduction in membrane microvilli. The suppression of uptake was reversible provided that sufficient time was allowed for the cells to recover. The mechanism of this inhibition may be associated with energy-linked processes, as uptake of taurocholate, ouabain, and 2-aminoisobutyric acid is energy requiring while uptake of CdCl2 and 3-O-methyl-D-glucose is not. Cellular ATP was reduced in a dose-dependent manner, but a marked depletion occurred only at cytotoxic concentrations. Na(+)-K(+)- and Mg2(+)-ATPase activities in hepatocyte plasma membrane preparations were also inhibited by solvent exposure. The data suggest that 1,1,1-trichloroethane and tetrachloroethylene interfere specifically with energy-dependent hepatic transport functions and that a decrease in ATP levels and/or inhibition of cell membrane ATPases may be the mechanism.