Alpha-naphthylisothiocyanate-induced elevation of serum bile acids: lack of causative effect on bile acid transport.
In recent years chemicals including chlorinated solvents have been found to interfere with the transport of bile acids (BA) by hepatocytes, which probably accounts for the raised serum bile acids (SBA) after exposure. However, the known cholestatic agent, alpha-naphthylisothiocyanate (ANIT) has never been fully examined for its effect on these processes. Accordingly, the direct effects in vitro and the effects of in vivo treatment on bile acid transport have been investigated in this study. Direct addition of ANIT (5-100 microns) to hepatocytes isolated from untreated rats did not result in any change in uptake or efflux of taurocholic acid (TC), one of the most obviously elevated SBA in ANIT-treated rats. Additionally, accumulation of TC over an extended incubation period was not affected by ANIT. In vivo treatment with ANIT (50 mumol/kg i.p. on each of 3 consecutive days) resulted in a marked elevation of total serum bile acids (TSBA) and a slight increase in the activity of serum alkaline phosphatase (ALP) and a very mild hyperbilirubinemia, while other markers of liver injury were unaltered. In hepatocytes isolated from these rats, Km and Vmax for uptake and V0 for efflux were no different between ANIT and vehicle-treated animals. In conclusion, ANIT showed no effects on transport of BA on in vitro exposure or after treatment in vivo where SBA were clearly elevated. The lack of effects of ANIT on transport of bile acids is consistent with other postulated mechanisms of action. Furthermore, this indicates that the effects noted with solvents are not necessarily replicated by substances known to cause histopathological cholestasis.
Neghab
M
M
Toxicology Unit, National Institute of Occupational Health and Safety Worksafe Australia, University of Sydney, NSW, Australia.
Stacey
N H
NH
D015058:1-Naphthylisothiocyanate / Q000494:pharmacology*; D000410:Alanine Transaminase / Q000097:blood; D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D001647:Bile Acids and Salts / Q000097:blood / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002779:Cholestasis / Q000378:metabolism / Q000503:physiopathology; D007700:Kinetics; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008099:Liver / Q000378:metabolism*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013656:Taurocholic Acid / Q000378:metabolism
D001647:Bile Acids and Salts; D015058:1-Naphthylisothiocyanate; D013656:Taurocholic Acid; D007770:L-Lactate Dehydrogenase; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase