J. Singh et Rk. Reen, In vitro assessment of paracetamol-induced toxicity in the rat reuber hepatoma H4IIEC3/G(-) cell line competent of xenobiotics metabolism, TOX VITRO, 13(6), 1999, pp. 897-903
H4IIEC3/G(-) cells, descendants of rat Reuber hepatoma, were characterized
for their response to paracetamol (acetaminophen; AAP) toxicity during log-
phase of growth. The cells in culture were found to contain high contents o
f constitutive and dexamethasone inducible rat cytochrome P4503A besides ot
her CYP members reported earlier. AAP produced dose-dependent decrease in c
ellular growth (50% at 0.7 mM). The drug steadily reduced the activity of U
DP-glucuronyltransferase (UGT) towards 3-hydroxybenzo[a]pyrene, decreased t
he contents of UDP-glucuronic acid (UDPGA) and significantly lowered GSH co
ntents with length of exposure. After 48 hr of treatment, the GSH Levels re
gistered a fall of 50% while UGT and UDPGA exhibited a moderate decline of
less than 25%. Decrease in the conjugation capacity of cells correlated wit
h LDH leakage in the medium. Three compounds of natural origin, silymarin,
kutkin and andrographolide at 10-20 mu M, offered relatively modest protect
ion ranging from 24 to 55% at best, against the growth inhibitory effect of
paracetamol. The hepatoma cells investigated appeared metabolically compet
ent to respond to AAP toxicity and might prove useful for screening of agen
ts against AAP-induced hepatotoxicity. (C) 1999 Elsevier Science Ltd. All r
ights reserved.