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Acetaminophen hepatotoxicity and targeted rescue: A model for specific chemotherapy of hepatocellular carcinoma
Author(s) -
Wu George Y.,
Wu Catherine H.,
Rubin Mark I.
Publication year - 1985
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.1840050502
Subject(s) - fetuin , acetaminophen , acetylcysteine , conjugate , asialoglycoprotein receptor , endocytosis , hepatocyte , glycoprotein , cell culture , pharmacology , in vitro , receptor , microbiology and biotechnology , chemistry , biology , biochemistry , antioxidant , mathematical analysis , genetics , mathematics
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.