Toxicological Sciences, Vol 47, 203-210, Copyright © 1999 by Society of Toxicology
DJ Orsler, J Ahmed-Choudhury, JK Chipman, T Hammond and R Coleman
alpha-Naphthylisothiocyanate (ANIT) induces intrahepatic cholestasis in
rats, involving damage to biliary epithelial cells; our study aims to
investigate whether disruption of biliary function in hepatocytes can
contribute to early stages of ANIT-induced intrahepatic cholestasis.
Isolated rat hepatocyte couplets were used to investigate biliary function
in vitro by canalicular vacuolar accumulation (cVA) of a fluorescent bile
acid analogue, cholyl-lysyl-fluorescein (CLF), within the canalicular
vacuole between the two cells. After a 2-h exposure to ANIT, there was a
concentration-dependent inhibition of cVA (cVA-IC50; 25 microM), but no
cytotoxicity (LDH leakage or [ATP] decline) within this ANIT concentration
range. There was no loss of cellular [GSH] at low ANIT concentrations, but,
at 50 microM ANIT, a small but significant loss of [GSH] had occurred.
Diethylmaleate (DEM) partially depleted cellular [GSH], but addition of 10
microM ANIT had no further effect on GSH depletion. Reduction in cVA was
seen in DEM-treated cells; addition of ANIT to these cells reduced cVA
further, but the magnitude of this further reduction was no greater than
that caused by ANIT alone, indicating that glutathione depletion does not
enhance the effect of ANIT. F-actin distribution (by phalloidin-FITC
staining) showed an increased frequency of morphological change in the
canalicular vacuoles but only a small, non-significant (0.05 < p <
0.1) increase in proportion of the F-actin in the region of the
pericanalicular web. The results are in accord with a disruption of
hepatocyte canalicular secretion within two h in vitro, at low, non-
cytotoxic concentrations of ANIT, and the possible involvement of a
thiocabamoyl-GSH conjugate of ANIT (GS-ANIT) in this effect.
ARTICLES
ANIT-induced disruption of biliary function in rat hepatocyte couplets
School of Biochemistry, University of Birmingham, Edgbaston, U.K.
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