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

Raised concentrations of serum bile acids (SBA) following occupational exposure to a number of halogenated aliphatic hydrocarbon solvents an d after in vivo exposure of experimental animals to these substances h ave been reported in several studies in recent years. However, the wid ely used nonchlorinated aromatic hydrocarbon solvent, toluene, has not been critically examined for its effect on serum bile acids. Accordin gly, the effect of in vivo treatment with toluene on SBA and its direc t in vitro effects on the transport of bile acids by isolated rat hepa tocytes were investigated in this study. In vivo treatment with toluen e (2.3 mmol/kg body weight, ip, on each of 3 consecutive days) resulte d 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 en zymes. In vitro application of noncytotoxic doses of toluene in the va por phase to hepatocytes isolated from untreated rats resulted in a si gnificant inhibition of the initial rate (V-0) of uptake of cholic aci d (CA). Similarly, accumulation of CA and taurocholic acid (TC) over a n extended incubation time by hepatocytes exposed to toluene was signi ficantly inhibited. Kinetic analysis revealed a noncompetitive inhibit ion of CA uptake as suggested by a decline in V-max and an unaltered K -m. In contrast, the initial rate of efflux of these substrates and th eir continuous efflux from preloaded cells were unaffected by exposure to toluene. Thus, toluene exposure inhibited the transport and accumu lation of bile acids by hepatocytes in a manner largely similar to tha t of halogenated solvents, and this inhibition could explain the raise d 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 evi dence of liver injury as measured by liver enzyme tests) were reported in workers following occupational exposure to this solvent. Additiona lly, in full agreement with our previous investigations in which SBA l evels were found to be a sensitive biological marker of exposure to ha logenated aliphatic hydrocarbon solvents, the data support a similar r ole for SBA on exposure to toluene as well.