TOLUENE-INDUCED ELEVATION OF SERUM BILE ACIDS: RELATIONSHIP TO BILE ACID TRANSPORT

Abstract

Raised concentrations of serum bile acids (SBA) following occupational exposure to a number of halogenated aliphatic hydrocarbon solvents and after in vivo exposure of experimental animals to these substances have been reported in several studies in recent years. However, the widely used nonchlorinated aromatic hydrocarbon solvent, toluene, has not been critically examined for its effect on serum bile acids. Accordingly, the effect of in vivo treatment with toluene on SB A and its direct in vitro effects on the transport of bile acids by isolated rat hepatocytes were investigated in this study. In vivo treatment with toluene (2.3 mmol/kg body weight, ip, on each of 3 consecutive days) resulted in a significant rise in the serum concentrations of total and some individual bile acids while other parameters of hepatobiliary function were unaltered. Administration of a higher dose of solvent (9.2 mmol/kg body weight, ip) resulted in a further increase in total SBA levels together with a significant rise in serum activities of some liver enzymes. In vitro application of noncytotoxic doses of toluene in the vapor phase to hepatocytes isolated from untreated rats resulted in a significant inhibition of the initial rate (Vo) of uptake of cholic acid (CA). Similarly, accumulation of CA and taurocholic acid (TC) over an extended incubation time by hepatocytes exposed to toluene was significantly inhibited. Kinetic analysis revealed a noncompetitive inhibition of CA uptake as suggested by a decline in Vmax and an unaltered Km. In contrast, the initial rate of efflux of these substrates and their continuous efflux from preloaded cells were unaffected by exposure to toluene. Thus, toluene exposure inhibited the transport and accumulation of bile acids by hepatocytes in a manner largely similar to that of halogenated solvents, and this inhibition could explain the raised SBA concentrations following in vivo exposure to this solvent. These findings are consistent with and provide mechanistic data to support previous studies where increased SBA levels (in the absence of any evidence of liver injury as measured by liver enzyme tests) were reported in workers following occupational exposure to this solvent. Additionally, in full agreement with our previous investigations in which SBA levels were found to be a sensitive biological marker of exposure to halogenated aliphatic hydrocarbon solvents, the data support a similar role for SBA on exposure to toluene as well.