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 of constitutive and dexamethasone inducible rat cytochrome P4503A besides other CYP members reported earlier. AAP produced dose-dependent decrease in cellular growth (50% at 0.7mm). The drug steadily reduced the activity of UDP-glucuronyltransferase (UGT) towards 3-hydroxybenzo[a]pyrene, decreased the contents of UDP-glucuronic acid (UDPGA) and significantly lowered GSH contents with length of exposure. After 48hr of treatment, the GSH levels registered a fall of 50% while UGT and UDPGA exhibited a moderate decline of less than 25%. Decrease in the conjugation capacity of cells correlated with LDH leakage in the medium. Three compounds of natural origin, silymarin, kutkin and andrographolide at 10-20 mum, offered relatively modest protection ranging from 24 to 55% at best, against the growth inhibitory effect of paracetamol. The hepatoma cells investigated appeared metabolically competent to respond to AAP toxicity and might prove useful for screening of agents against AAP-induced hepatotoxicity.
Singh
J
J
Biochemistry Section, Division of Pharmacology, Regional Research Laboratory (CSIR), Canal Road, Jammu Tawi-180001, India.
Reen
R K
RK