Acetaminophen hepatotoxicity and targeted rescue: a model for specific chemotherapy of hepatocellular carcinoma.
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.
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D000082:Acetaminophen / Q000009:adverse effects*; D000111:Acetylcysteine / Q000627:therapeutic use*; D037263:Asialoglycoprotein Receptor; D001212:Asialoglycoproteins / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D002460:Cell Line; D004705:Endocytosis; D006801:Humans; D007399:Interphase; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008954:Models, Biological; D019038:Platelet Glycoprotein GPIb-IX Complex; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface / Q000502:physiology*; D011971:Receptors, Immunologic / Q000502:physiology
D037263:Asialoglycoprotein Receptor; D001212:Asialoglycoproteins; D019038:Platelet Glycoprotein GPIb-IX Complex; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; C032193:glycoprotein receptor GPIb-IX; D000082:Acetaminophen; D000111:Acetylcysteine