Effects of carbon tetrachloride and chloroform on bile acid transport in isolated rat hepatocytes: Relationship to elevated serum bile acids.
The hepatotoxic effects of chlorinated hydrocarbon solvents have been well recognized for many years. More recently serum bile acids (SBA) have been considered as a sensitive indicator for the determination of liver dysfunction. However, changes in SBA could result from interference with hepatic transport processes. In this study, the effects of carbon tetrachloride (CCl(4)) and chloroform (CHCl(3)) on uptake and efflux of bile acids were examined in isolated rat liver cells to determine whether this may play a role in elevated SBA after CCl(4) or CHCl(3) treatment. Cholic acid (CA) and taurocholic acid (TC) were selected as representative bile acids known to enter hepatocytes by active transport. At none of the doses of CCl(4) and CHCl(3) investigated was there a significant change in cytoplasmic enzymes or intracellular K(+) release. CCl(4) and CHCl(3) were both found to cause a dose-related inhibition of uptake of CA and TC. Furthermore, CCl(4) and CHCl(3) were shown to increase the Michaelis constant (K(m)) but leave maximum velocity (V(max)) unchanged thus indicating competitive inhibition. The lowest doses of CCl(4) and CHCl(3) at which inhibition of initial uptake rate (V(0)) occurred for CA or TC were found to be 0.5 mul/flask (0.07 mm) or 1.0 mul/flask (0.17 mm) in cell suspensions, respectively. The inhibition of uptake could be reversed 30 min after cessation of exposure to CCl(4). No chemical-induced interference of efflux for CA or TC was found in preloaded cells. These findings indicate that interference in bile acid uptake may be involved, at least in part, in the increases in SBA in dosed animals, or workers exposed to CCl(4), CHCl(3) and perhaps other chlorinated solvents.
Bai
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CL
Toxicology Unit, National Institute of Occupational Health and Safety (Worksafe Australia), The University of Sydney, NSW 2006, Australia.
Stacey
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NH