In vitro interference with hepatocellular uptake of bile acids by xylene

Abstract

Occupational exposure to a mixture of two widely used aromatic hydrocarbon solvents, xylene and toluene, has been associated with a significant rise in the concentrations of serum bile acids (SBA). We have recently shown that toluene interferes with the transport of bile acids by hepatocytes and this could explain elevated SBA after occupational exposure or following in vivo administration of this compound to experimental animals. However, it is not known if xylene, like its monomethylated homologue, toluene, could interfere with the processes of bile acid transport by hepatocytes. Therefore, the present studies were undertaken to examine this possibility. Direct addition of a non-cytotoxic dose ( 2.5 μ1 2.8 × 10 6 cells) of xylene (in vapour phase) to hepatocytes isolated from untreated rats significantly inhibited the initial rates (determined from slope of the lines in the linear range (20–80 s)) of uptake (V 0) of 10 μ M cholic acid (CA) and-taurocholic acid (TC) by 37 and 48%, respectively ( P < 0.05). Similarly, accumulation of these substrates by hepatocytes over an extended incubation time up to 30 min was significantly inhibited to the same extent by xylene exposure. This inhibitory effect was found to be reversible when sufficient time was allowed for the cells to recover. In contrast, the initial rates (V 0) of efflux (determined from slope of the lines in the linear range (1–5 min)) of these bile acids (25 μM) and their continuous efflux (up to 30 min) from preloaded cells incubated with a similar dose of xylene were not (except for the 1 min time point) significantly different from those of controls. In conclusion, xylene interferes with the transport of bile acids by hepatocytes in a manner largely similar to that of its monomethylated homologue, toluene. These findings extend our previous observations on aliphatic and aromatic hydrocarbon solvents and provide mechanistic data at a cellular level to support a causal role for xylene (as well as toluene) in raised SBA levels of exposed individuals.