In vitro assessment of paracetamol-induced toxicity in the rat reuber hepatoma H4IIEC3/G(-) cell line competent of xenobiotics metabolism

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.