Acute administration of
alpha-naphthylisothiocyanate (ANIT) to rats has been used as a model of
intrahepatic cholestasis. The mechanism of toxicity of ANIT is unknown, although recent evidence suggests a causal or permissive role for
glutathione (GSH) (Dahm LJ and Roth RA, Biochem Pharmacol 42: 1181-1188, 1991). In these studies, ANIT treatment elevated hepatic non-
protein sulfhydryl (NPSH) content, an
indicator of GSH content, when liver injury was evident. The purpose of the present study was to characterize the effects of ANIT on hepatic NPSH content and to relate these changes to the development of liver injury. In rats fasted for 24 hr, administration of ANIT (100 mg/kg, per os [p.o.]) did not change hepatic NPSH content, bile flow, or serum measurements of total
bilirubin concentration,
alanine aminotransferase (ALT) activity, or
gamma-glutamyltransferase (GGT) activity by 12 hr post-treatment relative to
corn oil vehicle controls. However, by 24 hr after ANIT treatment, rats exhibited
cholestasis and elevations in
serum markers of liver injury. These markers were associated temporally with an increase in hepatic NPSH content, which consisted entirely of GSH. To determine whether the
cholestasis caused by ANIT treatment might have caused the elevation of hepatic NPSH content, an
extrahepatic cholestasis in rats was produced by
ligation of the common bile duct. Bile duct
ligation elevated hepatic NPSH content between 6 and 12 hr after
ligation. Administration to rats of a non-hepatotoxic analog of ANIT,
beta-naphthylisothiocyanate, also elevated hepatic NPSH content 24 hr
after treatment. Taken together, these results indicate that the elevation in hepatic NPSH content after ANIT treatment is associated temporally with the onset of liver injury, but this elevation does not appear to participate causally in the mechanism of injury.