Acetaminophen hepatotoxicity and targeted rescue: a model for specific chemotherapy of hepatocellular carcinoma

Abstract

We have taken advantage of the presence of hepatic receptors for galactose-terminal (asialo-)glycoproteins to achieve targeted rescue of differentiated hepatocytes from acetaminophen-induced toxicity in vitro. To accomplish this, a conjugate was formed by covalent coupling of N-acetylcysteine (an acetaminophen antagonist) to galactose-terminal (asialo-)fetuin. We used two human hepatocyte-derived cell lines to test our targeted-rescue method: Hep G2 cells are capable of receptor-mediated endocytosis of galactose-terminal glycoproteins and PLC/PRF/5 cells are not. In the presence of acetaminophen alone, both cell lines demonstrated a similar concentration-dependent sensitivity. Growth rates of both cell lines became normal when N-acetylcysteine was administered in equimolar quantities with acetaminophen indicating that both cell lines had the potential of responding to the antagonist. When asialofetuin-N-acetylcysteine conjugate was given to both cell lines in the presence of acetaminophen, PLC/PRF/5, receptor (-) cells failed to respond. However, Hep G2, receptor (+) cells treated with asialofetuin-N-acetylcysteine conjugate under identical conditions, increased their populations and eventually reached confluence. Control conjugate fetuin-N-acetylcysteine as well as asialofetuin alone had no effect on either cell line.